Project 3: Roles of Tau Levels, Sequence and Interactors in Neural Network Dysfunction of Alzheimer's Disease

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PROJECT 3 – SUMMARY Tau contributes to Alzheimer’s disease (AD) and many other brain diseases. However, it is uncertain how tau causes neuronal dysfunction and degeneration, in part because experimental models are not optimized to compare the relative pathogenicity of different tau species in disease-relevant contexts. Mutations in MAPT, the gene encoding tau, cause frontotemporal lobar degeneration (FTLD) instead of AD. In contrast, the rare A152T variant of tau increases risk for both types of diseases. These associations merit further exploration, especially as models expressing FTLD-mutant tau are widely used to study tau in AD and to develop novel AD treatments. Clinical AD onset is preceded by abnormal accumulations of amyloid-b (Ab) peptides in brain, and many AD patients have at least one apolipoprotein (apo) E4 allele, the most important genetic risk factor for AD. Therefore, we will generate new mouse models combining human Ab and apoE4 expression with near-physiological levels of human tau that is (1) wildtype, as in most AD patients, (2) carries the A152T substitution, which increases AD risk, or (3) bears the P301S mutation, which causes FTLD and is widely used in overexpression models. Comprehensive functional, pathological, and transcriptomic analyses of the new models, in collaboration with Projects 1, 2, and 4 and Core B, should yield new insights into differential effects of these tau species and their roles in the pathogenesis of dementia. We hypothesize that tau species that increase AD risk or cause FTLD differ in their effects on the integrity and function of neurons and neural networks, especially when combined with Aβ and apoE4. Until we know which forms of tau are most pathogenic in different conditions, the most pragmatic therapeutic approach to tau in our view is partial reduction of overall tau levels, which is well tolerated and has benefits in conventional models. We will therefore use tau-targeting antisense oligonucleotides (ASOs) to (1) determine whether reducing human tau can diminish neural network dysfunction, neurodegeneration and cognitive decline in models co-expressing human Ab and apoE4, (2) define the optimal timing for this intervention, and (3) reveal the most critical co-pathogenic mechanisms of tau. We hypothesize that ASO- mediated tau reduction will diminish not only tau pathology in one or more of the new models, but also synaptic deficits, neural network dysfunction, and cognitive deficits, even though it is unlikely to reduce amyloid deposition or plaque-associated microgliosis. This experiment should help determine when tau reduction must be initiated relative to the onset of cognitive deficits for it to have therapeutic benefits in AD-relevant contexts. Single- nucleus/single-cell transcriptomic analyses will be used to identify cell-type-specific gene expression changes and novel molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of tau reduction. These analyses will also help Projects 1 and 2 distinguish between pathogenic mechanisms of apoE4 and Ab that do or do not depend on tau and could identify novel molecular and cellular mechanisms that mediate tau sequence-specific effects in the absence or presence of AD-relevant co-pathogens.