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daily 0.75 2021-05-24 https://www.muckelab.com/drug-development-efforts daily 0.75 2021-05-24 https://www.muckelab.com/brain-disorders daily 0.75 2024-09-05 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/f4c7aed5-f676-4e96-a7c1-8d5b271ade4a/iStock-1270947193+edited.jpg https://www.muckelab.com/new-page-2 daily 0.75 2021-05-24 https://www.muckelab.com/microscopy daily 0.75 2021-05-24 https://www.muckelab.com/news daily 0.75 2025-08-27 https://images.squarespace-cdn.com/content/v1/5ce435d6bea1ed00016ba287/1558964652247-5MWXNMFZVOPGE4TY6U2Q/MHeiderich_ReflexionenZwei-05-copy.jpg News https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/34fd5b22-c9f3-42a5-b6c5-013feff08086/nomis_hero.png News - Fueling Discovery at the Frontiers of Neuroscience: The NOMIS-Gladstone Fellowship Program August 21, 2025 | Article The NOMIS-Gladstone Fellowship Program was launched in 2024 by the NOMIS Foundation and the Gladstone Institutes. Designed to empower fearless early-career scientists with a deep passion for fundamental discovery in neuroscience, the program catalyzes bold explorations of key mechanisms governing brain functions and dysfunctions—where disciplines converge and discoveries abound. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/f53db5f8-ed95-44a2-9431-4e644d3ecf49/gladstone_voskobiynykyuliya-hero.jpeg News - When Brain Cells Talk: NOMIS-Gladstone Fellow Yuliya Voskobiynyk on Decoding Microglia’s Secret Signals August 21, 2025 | Article “When I mention I study how brain immune cells talk to neurons, the response is usually a polite nod or a surprised “Wait, aren’t those just for fighting infection?” That’s the twist. In the brain, these cells don’t just fight. They listen. They whisper. They respond. And sometimes, they ignite chaos. Their conversations with neurons could help us understand the brain and its diseases, including epilepsy and Alzheimer’s.” https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/7be734ff-eaf2-48ec-bc5b-05295ecb8a91/_bbb7534.jpg News - Powerful New Tool Can Identify Cells Promoting Health or Disease April 7, 2025 | Press Release Gladstone scientists developed a computational approach that accurately distinguishes cells of different identities or characteristics in complex biological samples used in diverse areas of biomedical and discovery research. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/80cf85f3-7e04-466b-8361-0614c4fad240/Screenshot+2024-10-04+at+11.17.51+AM.png News - Hope for Alzheimer’s: A Conversation with Gladstone’s Lennart Mucke September 9, 2024 | Article Mucke, director of the Gladstone Institute of Neurological Disease, discusses what’s next for Alzheimer’s research, the role of nonprofit research in developing new therapies, and why he’s more hopeful than ever for a future where neurodegenerative diseases are fully treatable—and even preventable. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/754348cc-98eb-4a59-a672-2e478a6dcc72/gladstone_gind25_hero.jpg News - A Quarter Century of Disease-Focused Neuroscience October 3, 2023 | Article A quarter century ago, in September 1998, Gladstone Institutes launched the Gladstone Institute of Neurological Disease. In 2023, it brought together investigators and alumni to celebrate the institute’s 25th anniversary, reflect on landmark scientific achievements, and look ahead at the future of disease-focused neuroscience. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/cc52b3a8-e5bc-4bd5-9483-602777e9f33c/Gladstone_DasMelanie-MuckeLennart.jpg News - In Alzheimer Brain, Can Synaptic Pruning Be Good? September 8, 2023 | Press Release Alzforum—Loss of synapses in the brain is associated with progression of Alzheimer’s disease (AD). However, a new study shows that in mice, a mutation associated with increased risk of AD results in an excess of synapses. In conjunction with recent work from a few other groups, this suggests that removal of synapses may actually play a protective role against AD, at least early in the disease process. Shown here is the study’s first author, Melanie Das (left), and Lennart Mucke (right). https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/ba7de9e0-9b97-4f4b-a5b0-7edc5f67766e/_AAA6935.jpeg News - Zeroing in on a New Treatment for Autism and Epilepsy April 27, 2022 | Press Release Scientists in Lennart Mucke’s lab at Gladstone report new findings that could guide the development of better therapeutic strategies for Dravet syndrome and related conditions. Shown here are the study’s first authors, Eric Shao (left) and Che-Wei Chang (right). https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/4caa94f4-c13d-48de-aab7-af7c4dfa3e98/gladstone_muckelab_isciencehero.jpg News - Alzheimer’s Disease May Cause Vicious Circle between Brain Network and Immune Cell Dysfunctions October 26, 2021 | Press Release Gladstone scientists identified treatments to block subtle epileptic activity and chronic brain inflammation in a mouse model of Alzheimer’s disease. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/14e3f2ee-88c4-421c-b0c2-0a67b83d0166/Screenshot+2024-06-25+at+10.06.49+AM.jpg News - Maintaining Balance in the Brain October 19, 2021 | Press Release Gladstone scientists help explain how reducing the protein tau can prevent abnormal brain activity associated with Alzheimer’s disease, autism, and epilepsy. Shown here is the study’s first author, Che-Wei Chang. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/574b8f7c-102a-4189-8d39-50d28c502945/Takeda+press+release.jpeg News - Gladstone Neuroscience Researcher Elected to the National Academy of Medicine October 18, 2021 | Article Lennart Mucke is recognized for his leading role in defining molecular and pathophysiological mechanisms by which Alzheimer’s disease causes synaptic failure, neural network dysfunctions, and cognitive decline. “Such achievements usually reflect the contributions of many. My former and current coworkers share this honor with me.” – Lennart Mucke https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/a5bdbd31-68f3-4e03-8df0-6b313a400de2/Screenshot+2024-07-22+at+10.12.49+AM.png News - Current and Future Strategies to Treat and Prevent Alzheimer’s Disease June 16, 2020 | Video With an estimated 44 million diagnosed with Alzheimer’s disease worldwide, research is moving quickly to better understand the disease. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/5f48d95e-2d98-42e3-a795-ed06cedfe423/Share-Image3.jpg News - Autism Symptoms Improved in Mice by Reducing Alzheimer’s Disease Protein March 3, 2020 | Article GEN—Genetic Engineering and Biotechnology News reports on a recent study from the lab of Lennart Mucke that shows how reducing levels of Tau, a protein associated with Alzheimer’s disease, could prevent some symptoms of autism. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/d00f33bf-60df-4e01-a29a-53a1e14e0ea6/mucke-chao-tai.jpg News - Could Targeting an Alzheimer’s-Associated Protein Prevent Autism? March 2, 2020 | Press Release New study shows reducing levels of the protein tau prevents core autism symptoms in animal models. Shown here is Lennart Mucke (left), and the study’s first author, Chao Tai (right). https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/688a87ca-e4ce-423f-abb8-9b899201156f/Share-Image2.jpg News - Alzheimer’s Protein Turns up as Potential Target for Autism Treatments March 2, 2020 | Article Spectrum—Lowering the levels of a protein called tau, best known for its involvement in Alzheimer’s disease, eases autism-like traits in mice, according to a study from the lab of Lennart Mucke. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/896727d7-8d8e-4dc2-b039-811a5fa956c2/lennart-mucke-gladstone_900x506x2164-1220-0-213.jpg News - Alzheimer's target also could halt autism, Gladstone researchers show March 2, 2020 | Article San Francisco Business Times—A protein linked to Alzheimer's disease may play a role in some forms of autism spectrum disorder, potentially unlocking research into new drugs and expanding the market for therapies now in clinical trials. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/876c22d8-ebc2-49b8-b6ed-af025f76439f/Gladstone_ZhuLei_MuckeLab.jpg News - New Insights into the Aging Brain November 5, 2018 | Press Release A group of scientists decided to investigate why the choroid plexus contains so much more klotho than other brain regions. In a new study published in PNAS, they showed that klotho functions as a gatekeeper that shields the brain from the peripheral immune system. Shown here is the study’s first author, Lei Zhu. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/db2325f7-bdeb-4585-ba9c-fd9eb47c4b8f/gladstone-epilepsy-research.png News - Leading the Way to Better Treatments for People with Epilepsy March 26, 2021 | Article Gladstone researchers harness unique tools and perspectives to pave the way to more and better treatment options for epilepsy. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/5512815a-6b3b-457a-a93b-afd551eed582/Share-Image1.jpg News - Tau: A Promising Target to Treat Alzheimer’s Disease October 24, 2017 | Article Gladstone scientists receive funding to develop new drugs to reduce tau levels in the brain. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/77bb5f80-7605-48b0-b631-6bfaa30299a5/Picture1.jpg News - Conducting the Brain’s Symphony November 12, 2016 | Article Gladstone scientists discover how to control the cacophony of electrical activity in the brain, stopping seizures and reducing deficits related to Alzheimer’s disease. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/546872ec-a56a-4d57-8f96-26cfd47ea4b9/Picture12.jpg News - Considering Dementia from All Angles June 9, 2016 | Article Scientists at the Gladstone Institutes take a comprehensive approach to dementia research, pursuing several potential causal factors of the disease in the hopes of discovering breakthrough treatments. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/244a0b9f-d347-4360-865b-3edfe3e6b3eb/Picture13.jpg News - Profile: Sumihiro Maeda, PhD April 27, 2016 | Article Sumihiro Maeda, a research scientist at Gladstone, shares how his curiosity about where imagination and creativity come from led his path to study Alzheimer’s disease. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/5f48d95e-2d98-42e3-a795-ed06cedfe423/Share-Image3.jpg News - Reasons to Be Hopeful December 14, 2015 | Article New findings about Alzheimer’s disease advance the search for more effective treatments. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/733b7e68-1e11-44bc-b943-bbf336c6cf35/Picture14.jpg News - Alzheimer’s: Moving Towards a Cure August 4, 2015 | Video Hear Lennart Mucke, MD, Director of the Gladstone Institute of Neurological Disease, discuss progress towards Alzheimer’s cures during his recent City Arts & Lectures appearance. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/e96afa35-825d-42e8-93f6-943a74cd3132/Picture15.jpg News - Protein Linked to Longevity and Enhanced Cognition Also Protects Against Alzheimer’s Symptoms February 10, 2015 | Article Raising levels of the life-extending protein klotho can protect against learning and memory deficits in a mouse model of Alzheimer’s disease, despite the accumulation of Alzheimer-related toxins in the brain. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/1ddd6c70-8e29-48c0-aa85-bbc125159c18/Picture16.jpg News - Support Cells in the Brain Offer a New Strategy to Boost Memory January 25, 2015 | Article Researchers from the Gladstone Institutes have uncovered a new memory regulator in the brain involving adenosine receptors, which may offer a potential treatment to improve memory in Alzheimer’s disease. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/7cfbbddd-42ed-40df-bda9-819ad144edc1/Picture17.jpg News - Reduction of Tau Protein Improves Symptoms in Model of Severe Childhood Epilepsy August 13, 2014 | Article Researchers at the Gladstone Institutes have shown that reducing brain levels of the protein tau effectively blocks the development of disease in a mouse model of Dravet syndrome, a severe intractable form of childhood epilepsy. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/c201839d-12f4-4c6a-812f-fba4356c3de8/Picture18.jpg News - Better Cognition with Gene Variant Carried by 1 in 5 June 9, 2014 | Article A joint Gladstone-UCSF study reveals a gene linked to longevity also improves learning and memory. This discovery opens a new path for treating Alzheimer's and other aging-related diseases. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/896727d7-8d8e-4dc2-b039-811a5fa956c2/lennart-mucke-gladstone_900x506x2164-1220-0-213.jpg News - Gladstone Scientist to Receive Prestigious Pacesetter Award October 20, 2013 | Article Lennart Mucke, MD will receive the ARCS Foundation’s 2013 Pacesetter Award for his lifelong dedication to overcoming Alzheimer’s disease—and for mentoring students to take a similar approach. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/7cfbbddd-42ed-40df-bda9-819ad144edc1/Picture17.jpg News - Gladstone’s Lennart Mucke Wins MetLife Foundation Award May 14, 2013 | Article SAN FRANCISCO, CA—Lennart Mucke, MD, who directs neurological research at the Gladstone Institutes, today received the MetLife Foundation’s 2013 Award for Medical Research in Alzheimer’s Disease at a scientific briefing and awards ceremony in New York. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/688a87ca-e4ce-423f-abb8-9b899201156f/Share-Image2.jpg News - Gladstone Scientists Discover that Epilepsy Drug Reverses Memory Loss in Animal Model of Alzheimer’s Disease August 5, 2012 | Article Scientists at the Gladstone Institutes have discovered that an FDA-approved anti-epileptic drug reverses memory loss and alleviates other Alzheimer’s-related impairments in an animal model of the disease. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/896727d7-8d8e-4dc2-b039-811a5fa956c2/lennart-mucke-gladstone_900x506x2164-1220-0-213.jpg News - Gladstone’s Lennart Mucke Receives Lifetime Achievement Award from the Alzheimer’s Association July 14, 2012 | Article Lennart Mucke has received the Khalid Iqbal Lifetime Achievement Award for his exceptional contributions to Alzheimer's disease research. https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/5f48d95e-2d98-42e3-a795-ed06cedfe423/Share-Image3.jpg News - Gladstone Scientists Identify Key Network Mechanism That Could Contribute to Cognitive Problems in Alzheimer’s Disease April 25, 2012 | Article Scientists at the Gladstone Institutes have unraveled a process by which depletion of a specific protein in the brain contributes to the memory problems associated with Alzheimer's disease. https://www.muckelab.com/neural-network-dysfunctions daily 0.75 2021-05-24 https://www.muckelab.com/autism daily 0.75 2024-06-24 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/31fbacc1-d590-4cd0-a6a0-85833b98ad6d/Autism.jpeg Autism https://www.muckelab.com/translation daily 0.75 2024-09-05 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/b6389af7-d2ff-410a-9197-0cdb56f5e7ef/_AAA3260.jpg https://www.muckelab.com/dementias daily 0.75 2024-06-24 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https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/5845bc5d-75fa-469f-9c83-4e3d13e22b35/Picture2.png https://www.muckelab.com/gallery-3 daily 0.75 2023-03-01 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/7ce11267-56af-4f21-b8be-c30cfc815c17/brain+functions.jpeg Home Page with Gallery Brain Functions https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/45686b02-34a7-4fb7-9bc9-6c3d9f9ca662/brain+diseases.jpeg Home Page with Gallery Brain Diseases https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/355528e0-96f3-47d2-81f5-12eb18fe33e6/Screen+Shot+2023-02-23+at+1.33.30+PM.png Home Page with Gallery Disease Mechanisms https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/f288ea0e-45de-4a0d-985f-b27688e8ab56/Picture1.png Home Page with Gallery Translation https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/5845bc5d-75fa-469f-9c83-4e3d13e22b35/Picture2.png Home Page with Gallery Technologies https://www.muckelab.com/new-page-4 daily 0.75 2023-03-02 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/1677716323543-AWQLU3L7YSJOJ15WXJ0O/brain+functions.jpeg https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/45686b02-34a7-4fb7-9bc9-6c3d9f9ca662/brain+diseases.jpeg https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/355528e0-96f3-47d2-81f5-12eb18fe33e6/Screen+Shot+2023-02-23+at+1.33.30+PM.png https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/f288ea0e-45de-4a0d-985f-b27688e8ab56/Picture1.png https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/5845bc5d-75fa-469f-9c83-4e3d13e22b35/Picture2.png https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/1677716323543-AWQLU3L7YSJOJ15WXJ0O/brain+functions.jpeg https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/45686b02-34a7-4fb7-9bc9-6c3d9f9ca662/brain+diseases.jpeg 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https://www.muckelab.com/autism-1 daily 0.75 2024-06-24 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/7f85ae93-cb60-4d81-a6d6-6656fa12e251/Screenshot+2024-06-24+at+10.23.27+AM.jpg Intellectual disability https://www.muckelab.com/epilepsy-1 daily 0.75 2024-06-27 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/861d98d3-a456-44cc-8928-988d2a65bd98/learning+memory.jpg Learning, memory and problem solving https://www.muckelab.com/epilepsy-1-1 daily 0.75 2024-06-24 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/ef7e91d6-042c-4522-bd18-5c77baafe136/Modalities-of-social-communication-in-mice-Socio-emotional-interactions-are-mediated-by.png Social interactions and communication https://www.muckelab.com/publications daily 0.75 2026-03-19 https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/fb1b43f6-f71d-4934-8ebe-6dc901ec7085/Picture1.jpg Publications https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/b8c8f9da-77cb-4258-86f3-d98f4bb22895/13+Nature+Neuro-Suberbielle.png Publications https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/bbc614a7-ca07-4eae-b333-6cab7f59c773/Roberson-Science-Mucke.png Publications https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/34a157e1-2ae5-4fa4-aeb9-2d7a2cdbf3cd/07-+Palop+Mucke+JNeurosci.png Publications https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/49ed9b01-03cc-41c5-bf33-29613e4ac8fa/16-EMBO-Mucke.png Publications https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/4870b8f6-e021-40da-bf8d-4e4e908c9086/Screenshot+2025-01-08+at+11.33.11+AM.jpg Publications - CHOIR improves significant-based detection of cell types and states from single-cell data Cathrine Sant, Lennart Mucke, M. Ryan Corces Clustering is a critical step in the analysis of single-cell data, enabling the discovery and characterization of cell types and states. However, most popular clustering tools do not subject results to statistical inference testing, leading to risks of overclustering or underclustering data and often resulting in ineffective identification of cell types with widely differing prevalence. To address these challenges, we present CHOIR (cluster hierarchy optimization by iterative random forests), which applies a framework of random forest classifiers and permutation tests across a hierarchical clustering tree to statistically determine clusters representing distinct populations. We demonstrate the performance of CHOIR through extensive benchmarking against 15 existing clustering methods across 230 simulated and five real single-cell RNA sequencing, assay for transposase-accessible chromatin sequencing, spatial transcriptomic and multi-omic datasets. CHOIR can be applied to any single-cell data type and provides a flexible, scalable and robust solution to the challenge of identifying biologically relevant cell groupings within heterogeneous single-cell data. Nat. Gen. 57: 1309–1319 (2025) PubMed | Nature Genetics https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/d3aaf3df-5deb-4a2b-a450-b6811b5fd440/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Tau ablation in excitatory neurons and postnatal tau knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model Eric Shao, Che-Wei Chang, Zhiyong Li, Xinxing Yu, Kaitlyn Ho, Michelle Zhang, Xin Wang, Jeffrey Simms, Iris Lo, Jessica Speckart, Julia Holtzman, Gui-Qiu Yu, Erik D Roberson, Lennart Mucke Intracellular accumulation of tau aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of tau is beneficial also in models of other brain disorders that lack such tau pathology, suggesting a pathogenic role of nonaggregated tau. Here, conditional ablation of tau in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy (SUDEP), overactivation of the phosphoinositide 3-kinase–AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a tau-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which tau has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral tau reduction could have similar benefits, even when initiated postnatally. Sci. Transl. Med. 14(642): eabm5527 (2022) PubMed | Science Translational Medicine https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/96e595ec-1105-451f-bc2d-8afd14a19e86/371_abb8255_fa.jpeg Publications - Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies Che-Wei Chang, Eric Shao, Lennart Mucke The protein tau is implicated in several brain disorders, including Alzheimer's disease, suggesting that it could be a target of therapeutics. However, because it is unclear how the pleiotropic roles of tau lead to neural pathology in different brain diseases, drug development remains challenging. Chang et al. review the possible mechanisms of tau in brain diseases and possible paths forward to improving research and drug development. Science 371(6532):eabb8255 (2021) PubMed | Science https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/51953dfe-78f7-4c0a-a429-568624941747/fx1.jpeg Publications - Interdependence of neural network dysfunction and microglial alterations in Alzheimer's disease-related models Melanie Das, Wenjie Mao, Eric Shao, Soniya Tamhankar, Gui-Qiu Yu, Xinxing Yu, Kaitlyn Ho, Xin Wang, Jiaming Wang, Lennart Mucke Nonconvulsive epileptiform activity and microglial alterations have been detected in people with Alzheimer’s disease (AD) and related mouse models. However, the relationship between these abnormalities remains to be elucidated. We suppressed epileptiform activity by treatment with the antiepileptic drug levetiracetam or by genetic ablation of tau and found that these interventions reversed or prevented aberrant microglial gene expression in brain tissues of aged human amyloid precursor protein transgenic mice, which simulate several key aspects of AD. The most robustly modulated genes included multiple factors previously implicated in AD pathogenesis, including TREM2, the hypofunction of which increases disease risk. Genetic reduction of TREM2 exacerbated epileptiform activity after mice were injected with kainate. We conclude that AD-related epileptiform activity markedly changes the molecular profile of microglia, inducing both maladaptive and adaptive alterations in their activities. Increased expression of TREM2 seems to support microglial activities that counteract this type of network dysfunction. iScience 24(11): 103245 (2021) PubMed | iScience https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/636640fa-afca-4561-bab0-ba1519ec14ed/1-s2.0-S221112472101322X-fx1_lrg.jpg Publications - Tau reduction affects excitatory and inhibitory neurons differently, reduces excitation/inhibition ratios, and counteracts network hypersynchrony Che-Wei Chang, Mark D Evans, Xinxing Yu, Gui-Qiu Yu, Lennart Mucke The protein tau has been implicated in many brain disorders. In animal models, tau reduction suppresses epileptogenesis of diverse causes and ameliorates synaptic and behavioral abnormalities in various conditions associated with excessive excitation-inhibition (E/I) ratios. However, the underlying mechanisms are unknown. Global genetic ablation of tau in mice reduces the action potential (AP) firing and E/I ratio of pyramidal cells in acute cortical slices without affecting the excitability of these cells. Tau ablation reduces the excitatory inputs to inhibitory neurons, increases the excitability of these cells, and structurally alters their axon initial segments (AISs). In primary neuronal cultures subjected to prolonged overstimulation, tau ablation diminishes the homeostatic response of AISs in inhibitory neurons, promotes inhibition, and suppresses hypersynchrony. Together, these differential alterations in excitatory and inhibitory neurons help explain how tau reduction prevents network hypersynchrony and counteracts brain disorders causing abnormally increased E/I ratios. Cell Rep. 37(3):109855 (2021) PubMed | Cell Reports https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/d079d72b-9c5a-46ca-bd57-f54c84ea5dd6/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not inhibition of BACE1 Erik CB Johnson, Kaitlyn Ho, Gui-Qiu Yu, Melanie Das, Pascal E Sanchez, Biljana Djukic, Isabel Lopez, Xinxing Yu, Michael Gill, Weiping Zhang, Jeanne T Paz, Jorge J Palop, Lennart Mucke Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Mol. Neurodegener. 15:53, 1–26 (2020) PubMed | Molecular Neurodegeneration https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/ff01778e-75e4-43f0-b84a-dd75bac1c118/1-s2.0-S0896627320300659-gr3_lrg.jpg Publications - Tau reduction prevents key features of autism in mouse models Chao Tai, Che-Wei Chang, Gui-Qiu Yu, Isabel Lopez, Xinxing Yu, Xin Wang, Weikun Guo, Lennart Mucke Autism is characterized by repetitive behaviors, impaired social interactions, and communication deficits. It is a prevalent neurodevelopmental disorder, and available treatments offer little benefit. Here, we show that genetically reducing the protein tau prevents behavioral signs of autism in two mouse models simulating distinct causes of this condition. Similar to a proportion of people with autism, both models have epilepsy, abnormally enlarged brains, and overactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)/ mammalian target of rapamycin (mTOR) signaling pathway. All of these abnormalities were prevented or markedly diminished by partial or complete genetic removal of tau. We identify disinhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative PI3K regulator that tau controls, as a plausible mechanism and demonstrate that tau interacts with PTEN via tau’s proline-rich domain. Our findings suggest an enabling role of tau in the pathogenesis of autism and identify tau reduction as a potential therapeutic strategy for some of the disorders that cause this condition. Neuron 106(3):421–437.e112 (2020) PubMed | Neuron https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/bad8c767-d76e-41e5-b1b0-178208aef6ff/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease Niraj M Shanbhag, Mark D Evans, Wenjie Mao, Alissa L Nana, William W Seeley, Anthony Adame, Robert A Rissman, Eliezer Masliah, Lennart Mucke The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer’s disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI) or AD and from cognitively unimpaired controls. Immunostaining for γH2AX—a post-translational histone modification that is widely used as a marker of DSBs—revealed increased proportions of γH2AX-labeled neurons and astrocytes in the hippocampus and frontal cortex of MCI and AD patients, as compared to age-matched controls. In contrast to the focal pattern associated with DSBs, some neurons and glia in humans and mice showed diffuse pan-nuclear patterns of γH2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear γH2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear γH2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between γH2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear γH2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in γH2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of γH2AX formation may have different causes and consequences. We conclude that AD is associated with an accumulation of DSBs in vulnerable neuronal and glial cell populations from early stages onward. Because of the severe adverse effects this type of DNA damage can have on gene expression, chromatin stability and cellular functions, DSBs could be an important causal driver of neurodegeneration and cognitive decline in this disease. Acta Neuropathol. Commun. 7:77, 1–18 (2019) PubMed | Acta Neuropathologica Communications https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/ff451706-3d35-4321-a892-c70e546d8583/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Klotho controls the brain-immune system interface in the choroid plexus Lei Zhu, Liana R Stein, Daniel Kim, Kaitlyn Ho, Gui-Qiu Yu, Lihong Zhan, Tobias E Larsson, Lennart Mucke Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klothoflox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis. Proc. Natl. Acad. Sci. USA. 115:48, E11388–E11396 (2018) PubMed | PNAS https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/9d61968a-3e2a-45a8-8036-967258234005/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Istradefylline reduces memory deficits in aging mice with amyloid pathology Anna G Orr, Iris Lo, Heike Schumacher, Kaitlyn Ho, Michael Gill, Weikun Guo, Daniel H Kim, Anthony Knox, Takashi Saito, Takaomi C Saido, Jeffrey Simms, Carlee Toddes, Xin Wang, Gui-Qiu Yu, Lennart Mucke Adenosine A2A receptors are putative therapeutic targets for neurological disorders. The adenosine A2A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A2A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A2A receptor blockers might help counteract memory problems in patients with Alzheimer's disease. Neurobiol. Dis. 110: 29–36 (2018) PubMed | Neurobiology of Disease https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/c23a6793-efb2-4ead-bddd-e59ec0723253/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease Keith A Vossel, Kamalini G Ranasinghe, Alexander J Beagle, Danielle Mizuiri, Susanne M Honma, Anne F Dowling, Sonja M Darwish, Victoria Van Berlo, Deborah E Barnes, Mary Mantle, Anna M Karydas, Giovanni Coppola, Erik D Roberson, Bruce L Miller, Paul A Garcia, Heidi E Kirsch, Lennart Mucke, Srikantan S Nagarajan Seizures are more frequent in patients with Alzheimer's disease (AD) and can hasten cognitive decline. However, the incidence of subclinical epileptiform activity in AD and its consequences are unknown. Motivated by results from animal studies, we hypothesized higher than expected rates of subclinical epileptiform activity in AD with deleterious effects on cognition. Ann. Neurol. 80: 858–870 (2016) PubMed | Annals of Neurology https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/e94bd736-d0cd-4f03-9440-95ed94143a65/Screenshot+2024-07-22+at+9.27.26+AM.jpg Publications - Network abnormalities and interneuron dysfunction in Alzheimer disease Jorge J Palop and Lennart Mucke The function of neural circuits and networks can be controlled, in part, by modulating the synchrony of their components' activities. Network hypersynchrony and altered oscillatory rhythmic activity may contribute to cognitive abnormalities in Alzheimer disease (AD). In this condition, network activities that support cognition are altered decades before clinical disease onset, and these alterations predict future pathology and brain atrophy. Although the precise causes and pathophysiological consequences of these network alterations remain to be defined, interneuron dysfunction and network abnormalities have emerged as potential mechanisms of cognitive dysfunction in AD and related disorders. Here, we explore the concept that modulating these mechanisms may help to improve brain function in these conditions. Nat. Rev. Neurosci. 17: 777–792 (2016) PubMed | Nature Reviews Neuroscience https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/780c3de9-4572-49ed-b87b-dc2b9b563797/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Network dysfunction in α-synuclein transgenic mice and human Lewy body dementia Meaghan Morris, Pascal E Sanchez, Laure Verret, Alexander J Beagle, Weikun Guo, Dena Dubal, Kamalini G Ranasinghe, Akihiko Koyama, Kaitlyn Ho, Gui‐Qiu Yu, Keith A Vossel, Lennart Mucke Dementia with Lewy bodies (DLB) belongs to a family of common neurodegenerative diseases called synucleinopathies, which are pathologically characterized by the mislocalization and aggregation of the small, presynaptic protein α-synuclein (SYN). DLB, Parkinson's disease (PD), and Parkinson's disease with dementia (PDD) are closely related synucleinopathies, but are distinguished by differences in the relative onset of motor and cognitive impairments and in the distribution of SYN pathology. While much is known about the motor impairments in PD, very little is known about the mechanisms of cognitive impairment and cortical network dysfunction in DLB and PDD. DLB and PDD patients have dementia with visual hallucinations, attentional fluctuations, and parkinsonism. These symptoms are associated with a prominent slowing of cortical oscillations on electroencephalography (EEG), resulting in a shift in spectral power from higher (alpha, beta, gamma) to lower (delta, theta) frequency bands. However, it remains uncertain whether the neural network and cognitive dysfunction in these conditions are actually caused by SYN. Ann. Clin. Transl. Neurol. 2(11): 1012–1028 (2015) PubMed | Annals of Clinical and Translational Neurology https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/4eb48823-66df-4a34-98fe-0b551253b1ae/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Astrocytic adenosine receptor A2A regulates memory Anna G Orr, Edward C Hsiao, Max M Wang, Kaitlyn Ho, Daniel H Kim, Xin Wang, Weikun Guo, Jing Kang, Gui-Qiu Yu, Anthony Adame, Nino Devidze, Dena B Dubal, Eliezer Masliah, Bruce R Conklin, Lennart Mucke Astrocytes express a variety of G protein–coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss. Nat. Neurosci. 18:423–434 (2015) PubMed | Nature Neuroscience https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/3a33da3b-ec8d-4397-84e5-8c1e775eddde/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Tau reduction prevents disease in a mouse model of Dravet syndrome Ania L Gheyara, Ravikumar Ponnusamy, Biljana Djukic, Ryan J Craft, Kaitlyn Ho, Weikun Guo, Mariel M Finucane, Pascal E Sanchez, Lennart Mucke Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies. Ann. Neurol. 76(3): 443–456 (2014) PubMed | Annals of Neurology https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/727fbd7f-cce6-4f57-868e-b0f8879ec117/Screenshot+2024-06-24+at+4.01.09+PM.jpg Publications - Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model Pascal E Sanchez, Lei Zhu, Laure Verret, Keith A Vossel, Anna G Orr, John R Cirrito, Nino Devidze, Kaitlyn Ho, Gui-Qiu Yu, Jorge J Palop, Lennart Mucke In light of the rising prevalence of Alzheimer’s disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β–induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD. Proc. Natl. Acad. Sci. USA 109(42): E2895–E2903 (2012) PubMed | PNAS https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/23154134-7b8d-4ebd-8b2f-3fe944c53ccf/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Amyloid-β/Fyn–induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease Erik D Roberson, Brian Halabisky, Jong W Yoo, Jinghua Yao, Jeannie Chin, Fengrong Yan, Tiffany Wu, Patricia Hamto, Nino Devidze, Gui-Qiu Yu, Jorge J Palop, Jeffrey L Noebels, Lennart Mucke Alzheimer's disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn. We showed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded whole-cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit. J. Neurosci. 31(2): 700–711 (2011) PubMed | Journal of Neuroscience https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/4d171165-7c91-4a74-a40a-6072fa204b82/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network Julie A Harris, Nino Devidze, Laure Verret, Kaitlyn Ho, Brian Halabisky, Myo T Thwin, Daniel Kim, Patricia Hamto, Iris Lo, Gui-Qiu Yu, Jorge J Palop, Eliezer Masliah, Lennart Mucke The entorhinal cortex (EC) is one of the earliest affected, most vulnerable brain regions in Alzheimer's disease (AD), which is associated with amyloid-β (Aβ) accumulation in many brain areas. Selective overexpression of mutant amyloid precursor protein (APP) predominantly in layer II/III neurons of the EC caused cognitive and behavioral abnormalities characteristic of mouse models with widespread neuronal APP overexpression, including hyperactivity, disinhibition, and spatial learning and memory deficits. APP/Aβ overexpression in the EC elicited abnormalities in synaptic functions and activity-related molecules in the dentate gyrus and CA1 and epileptiform activity in parietal cortex. Soluble Aβ was observed in the dentate gyrus, and Aβ deposits in the hippocampus were localized to perforant pathway terminal fields. Thus, APP/Aβ expression in EC neurons causes transsynaptic deficits that could initiate the cortical-hippocampal network dysfunction in mouse models and human patients with AD. Neuron 68: 428–441 (2010) PubMed | Neuron https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/d637add4-26e5-4eb6-a236-40164ab2b0c4/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Cellular source of apolipoprotein E4 determines neuronal susceptibility to excitotoxic injury in transgenic mice Manuel Buttini, Eliezer Masliah, Gui-Qiu Yu, Jorge J Palop, Shengjun Chang, Aubrey Bernardo, Carol Lin, Tony Wyss-Coray, Yadong Huang, Lennart Mucke The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimer's disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforms in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms. Am. J. Pathol. 177: 563–569 (2010) PubMed | The American Journal of Pathology https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/a6f6d028-5805-4126-82f6-08ef9492573e/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model Erik D Roberson, Kimberly Scearce-Levie, Jorge J Palop, Fengrong Yan, Irene H Cheng, Tiffany Wu, Hilary Gerstein, Gui-Qiu Yu, Lennart Mucke Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions. Science 316(5825):750–754 (2007) PubMed | Science https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/cc91a032-6f3d-4628-bc2d-fdba2e831c29/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease Jorge J Palop, Jeannie Chin, Erik D Roberson, Jun Wang, Myo T Thwin, Nga Bien-Ly, Jong Yoo, Kaitlyn O Ho, Gui-Qiu Yu, Anatol Kreitzer, Steven Finkbeiner, Jeffrey L Noebels, Lennart Mucke Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP mice with high levels of amyloid-beta peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Abeta-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Abeta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD. Neuron 55: 697–711 (2007) PubMed | Neuron https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/44fe5f8d-da91-4760-9aef-0f34a0fb77bb/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation Irene H Cheng, Jorge J Palop, Luke A Esposito, Nga Bien-Ly, Fengrong Yan, Lennart Mucke The Arctic mutation within the amyloid-beta (Abeta) peptide causes Alzheimer disease. In vitro, Arctic-mutant Abeta forms (proto)fibrils more effectively than wild-type Abeta. We generated transgenic mouse lines expressing Arctic-mutant human amyloid precursor proteins (hAPP). Amyloid plaques formed faster and were more extensive in Arctic mice than in hAPP mice expressing wild-type Abeta, even though Arctic mice had lower Abeta(1-42/1-40) ratios. Thus, the Arctic mutation is highly amyloidogenic in vivo. Nat. Med. (11):1190–1192 (2004) PubMed | Nature Medicine https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/e5b226ad-7b71-45b7-b5e7-de699b8d0e12/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits Jorge J Palop, Brian Jones, Lisa Kekonius, Jeannie Chin, Gui-Qiu Yu, Jacob Raber, Eliezer Masliah, Lennart Mucke Transgenic mice expressing human amyloid precursor proteins (hAPP) and amyloid-beta peptides (Abeta) in neurons develop phenotypic alterations resembling Alzheimer's disease (AD). The mechanisms underlying cognitive deficits in AD and hAPP mice are largely unknown. We have identified two molecular alterations that accurately reflect AD-related cognitive impairments. Learning deficits in mice expressing familial AD-mutant hAPP correlated strongly with decreased levels of the calcium-binding protein calbindin-D28k (CB) and the calcium-dependent immediate early gene product c-Fos in granule cells of the dentate gyrus, a brain region critically involved in learning and memory. These molecular alterations were age-dependent and correlated with the relative abundance of Abeta1-42 but not with the amount of Abeta deposited in amyloid plaques. CB reductions in the dentate gyrus primarily reflected a decrease in neuronal CB levels rather than a loss of CB-producing neurons. CB levels were also markedly reduced in granule cells of humans with AD, even though these neurons are relatively resistant to AD-related cell death. Thus, neuronal populations resisting cell death in AD and hAPP mice can still be drastically altered at the molecular level. The tight link between Abeta-induced cognitive deficits and neuronal depletion of CB and c-Fos suggests an involvement of calcium-dependent pathways in AD-related cognitive decline and could facilitate the preclinical evaluation of novel AD treatments. Proc. Natl. Acad. Sci. U S A 100(16):9572–9577 (2003) PubMed | PNAS https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/d90122a2-bbd7-4e9d-9934-6f3dc611e4b0/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease Eliezer Masliah, Edward Rockenstein, Isaac Veinbergs, Yutaka Sagara, Margaret Mallory, Makoto Hashimoto, Lennart Mucke Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of β-amyloid and α-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human β-amyloid peptides, α-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before α-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more α-synuclein-immunoreactive neuronal inclusions than α-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in α-synuclein singly tg mice. β-Amyloid peptides promoted aggregation of α-synuclein in a cell-free system and intraneuronal accumulation of α-synuclein in cell culture. β-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of α-synuclein and exacerbating α-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of β-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated. Proc. Natl. Acad. Sci. USA 98: 12245–12250 (2001) PubMed | PNAS https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/7366e9b1-32e6-444d-98e7-e06febe682bb/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - High-level neuronal expression of Abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation Lennart Mucke, Eliezer Masliah, Gui-Qiu Yu, Margaret Mallory, Edward M Rockenstein, Gwen Tatsuno, Kang Hu, Dora Kholodenko, Kelly Johnson-Wood, Lisa McConlogue Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic Abeta peptides. The platelet-derived growth factor beta chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Abeta(1-42) levels, whereas an experimental mutation of the beta-secretase cleavage site (671(M-->I)) eliminated production of human Abeta. High levels of Abeta(1-42) resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Abeta levels but not with hAPP levels or plaque load. We conclude that Abeta is synaptotoxic even in the absence of plaques and that high levels of Abeta(1-42) are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Abeta toxicity plays an important role in the development of synaptic deficits in AD and related conditions. J. Neurosci. 20(11):4050–4058 (2000) PubMed | Journal of Neuroscience https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/63414c86-aea9-483a-b997-be3befcca491/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Alzheimer’s disease: Apolipoprotein E and cognitive performance Jacob Raber, Derek Wong, Gui-Qiu Yu, Manuel Buttini, Robert W Mahley, Robert E Pitas, Lennart Mucke Key proteins implicated in the development of Alzheimer's disease are the β-amyloid precursor protein, which gives rise to the β-amyloid peptides that accumulate in the deteriorating brain, and the different isoforms of apolipoprotein E (apoE). The apoE4 variant increases the risk of developing the disease compared with apoE3. We have tested the spatial memory of transgenic mice carrying human forms of these proteins and find that it is impaired in mice with apoE4 but not those with apoE3, even though the levels of β-amyloid in their brains are comparable. The fact that apoE3, but not apoE4, can protect against cognitive deficits induced by β-amyloid may explain why human apoE4 carriers are at greater risk of developing Alzheimer's than apoE3 carriers. Nature 404: 352–354 (2000) PubMed | Nature https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/9d3874b9-168e-4edb-a213-705f11f0fd5d/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models Albert Y Hsia, Eliezer Masliah, Lisa McConlogue, Gui-Qiu Yu, Gwen Tatsuno, Kang Hu, Dora Kholodenko, Robert C Malenka, Roger A Nicoll, Lennart Mucke Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid beta peptide, Abeta42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, Abeta peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased Abeta production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of Abeta that is independent of plaque formation. Proc. Natl. Acad. Sci. USA 96: 3228–3233 (1999) PubMed | PNAS https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/b03d0376-56ca-4451-97ba-e770d1db964a/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Isoform-specific effects of human apolipoprotein E on brain function revealed in Apoe knockout mice–Increased susceptibility of females Jacob Raber, Derek Wong, Manuel Buttini, Matthias Orth, Stefano Bellosta, Robert E Pitas, Robert W Mahley, Lennart Mucke Apolipoprotein E (apoE) mediates the redistribution of lipids among cells and is expressed at highest levels in brain and liver. Human apoE exists in three major isoforms encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with APOE epsilon2 and epsilon3, APOE epsilon4 increases the risk of cognitive impairments, lowers the age of onset of Alzheimer's disease (AD), and decreases the response to AD treatments. Besides age, inheritance of the APOE epsilon4 allele is the most important known risk factor for the development of sporadic AD, the most common form of this illness. Although numerous hypotheses have been advanced, it remains unclear how APOE epsilon4 might affect cognition and increase AD risk. To assess the effects of distinct human apoE isoforms on the brain, we have used the neuron-specific enolase (NSE) promoter to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE. Compared with NSE-apoE3 mice and wild-type controls, NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females. These findings demonstrate that human apoE isoforms have differential effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender. These results could be pertinent to cognitive impairments observed in human APOE epsilon4 carriers. NSE-apoE mice and similar models may facilitate the preclinical assessment of treatments for apoE-related cognitive deficits. Proc. Natl. Acad. Sci. USA 95: 10914–10919 (1998) PubMed | PNAS https://images.squarespace-cdn.com/content/v1/60abede39c83947ca4498f9a/14342c85-236c-4095-abda-c24ded7ada7f/Screenshot+2024-07-18+at+8.56.09%E2%80%AFPM.png Publications - Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer’s disease Tony Wyss-Coray, Eliezer Masliah, Margaret Mallory, Lisa McConlogue, Kelly Johnson-Wood, Carol Lin, Lennart Mucke Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease. 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