Molecular cascades causing brain disorders can start with inherited or acquired changes in genes whose protein products affect the function and integrity of brain cells. Proteins we study that are of particular relevance to Alzheimer’s disease and related disorders include the amyloid precursor protein (APP), Tau, apolipoprotein E (ApoE), and triggering receptor expressed on myeloid cells 2 (TREM2).

Abnormal accumulations of APP-derived amyloid-β (Aβ) peptides and of Tau form pathological hallmarks of Alzheimer’s disease: amyloid plaques and neurofibrillary tangles, respectively; and both pathologies are augmented by ApoE4, the main genetic risk factor for the most common form of this illness [1–2].

In experimental models, we made the surprising discovery that APP/Aβ, Tau, and ApoE4 can elicit neuronal deficits independent of plaques and tangles [3–8]. These findings fueled an interesting and still ongoing discussion in the field about whether the large protein aggregates that form in many neurodegenerative disorders actually cause neurological decline or reflect efforts to sequester highly bioactive proteins into more inert and less dangerous forms.

We also found that APP/Aβ causes not only synaptic depression, but also neural network hyperexcitability, and that both of these processes are enabled or augmented by Tau and ApoE4 [9–11, 2]. In mouse models for Alzheimer’s disease, we showed that reducing tau prevents neuronal and immune cell dysfunctions, revealing novel roles for tau in regulating neuronal activities and elucidating powerful links between APP/Aβ and Tau [12–14]. APP/Aβ-mediated pathogenic processes can now be integrated with those mediated by Tau.

Our long-standing research efforts in neuroimmunology have highlighted the importance of differentiating between beneficial and detrimental activities of non-neuronal brain cells such as astrocytes and microglia [15–19], particularly when it comes to the design of immune-modulatory treatments [20]. Different lines of investigation in the Mucke Lab have culminated in a unifying working model in which APP/Aβ and Tau engage neural network and immune cell dysfunctions in a vicious circle that contributes to synaptic impairments and cognitive decline [14, 21]. Therapeutic strategies that reduce the excitation/inhibition balance of neural networks or optimize the activity of immune cells can disrupt this circle [14].

For the brain to function effectively, it requires a good balance between excitation and inhibition at the levels of individual neurons, microcircuits, and broader networks. This excitation/inhibition (E/I) balance supports many important brain functions, but it can be disrupted by brain disease, resulting in neuronal and network hyperexcitability, which in turn can impair brain functions and escalate into epileptic activity [11].

We demonstrated that the protein Tau enables network hyperexcitability of diverse causes, including disease processes involved in dementias, primary epilepsies, and autism spectrum disorders. We also found that reducing tau levels in brain, or even just in excitatory neurons, can counteract the development of network hyperexcitability and behavioral abnormalities in mouse models of these conditions [12, 13, 22, 23, 14, 24]. These discoveries identified tau reduction as a promising strategy to block E/I imbalance in a range of neurologic and psychiatric conditions and challenging the long-standing notion that Tau aggregation causes neurodegeneration through loss of Tau functions [2].

We have also investigated the disease-promoting effects of α-synuclein, aggregates of which form so-called Lewy bodies in neurons of patients with Parkinson’s disease and dementia with Lewy bodies. Notably, over half of patients with Alzheimer’s disease also have Lewy body pathology. We showed that APP/Aβ can enhance the accumulation of α-synuclein in experimental models and found particularly strong evidence for network hyperexcitability in brains of Alzheimer’s disease patients who also had Lewy body pathology [25, 26].