The incidence of Alzheimer's disease (AD) is steadily increasing with the aging of the U.S. population, and there are still no highly effective treatments. Amyloid-? peptides (A?) and the microtubule-associated protein tau compose the pathological hallmarks of AD. Considerable effort has been devoted to development of anti- A? therapeutics, but disappointing results of early clinical trials has also broadened interest in other targets, notably tau. However, targeting a protein like tau that is abundant in the normal brain requires adequate knowledge of how it contributes to disease, and our understanding of tau's role in AD pathogenesis remains incomplete, hampering development of tau-based therapies for AD. We recently found that reducing tau expression has robust protective effects in multiple mouse models of AD, preventing cognitive deficits, premature mortality, impairment of synaptic plasticity, and epileptiform activity. These observations form the basis of the current application, capitalizing on this unique opportunity to understand how tau mediates or enables the effects of A?. This application uses a new conditional mouse model of tau reduction to address several questions related to tau's role downstream of A? in AD-related pathogenesis.
In Aim 1, we address the potential therapeutic relevance of tau reduction by determining if tau reduction in adulthood is protective in mouse models of AD.
In Aim 2, we address the cellular mechanisms underlying these effects by determining the effects of tau reduction in excitatory vs. inhibitory neurons.
In Aim 3, we test a hypothesized molecular mechanism for these protective effects by determining how tau reduction prevents altered expression of ion channels controlling cellular excitability.
Alzheimer's disease afflicts over 5 million people in the United States, imposing huge personal costs on patients and their families and tremendous financial costs on our health care system. The incidence of AD is projected to grow steadily over the next several decades due to aging of the US population. The proposed research addresses a potential mechanism for preventing the effects of the toxic proteins believed to cause Alzheimer's disease.
|Natelson Love, Marissa; Clark, David G; Cochran, J Nicholas et al. (2017) Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease. Neurobiol Aging 49:216.e7-216.e13|
|Kimbrough, Ian F; Robel, Stefanie; Roberson, Erik D et al. (2015) Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain 138:3716-33|
|Cochran, J Nicholas; Rush, Travis; Buckingham, Susan C et al. (2015) The Alzheimer's disease risk factor CD2AP maintains blood-brain barrier integrity. Hum Mol Genet 24:6667-74|
|Hall, Alicia M; Throesch, Benjamin T; Buckingham, Susan C et al. (2015) Tau-dependent Kv4.2 depletion and dendritic hyperexcitability in a mouse model of Alzheimer's disease. J Neurosci 35:6221-30|
|Arrant, Andrew E; Patel, Aashka R; Roberson, Erik D (2015) Effects of Exercise on Progranulin Levels and Gliosis in Progranulin-Insufficient Mice. eNeuro 2:|
|Cochran, J Nicholas; Diggs, Pauleatha V; Nebane, N Miranda et al. (2014) AlphaScreen HTS and live-cell bioluminescence resonance energy transfer (BRET) assays for identification of Tau-Fyn SH3 interaction inhibitors for Alzheimer disease. J Biomol Screen 19:1338-49|
|Warmus, Brian A; Sekar, Dheepa R; McCutchen, Eve et al. (2014) Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia. J Neurosci 34:16482-95|
|Li, Zhiyong; Hall, Alicia M; Kelinske, Mark et al. (2014) Seizure resistance without parkinsonism in aged mice after tau reduction. Neurobiol Aging 35:2617-2624|
|Cochran, J Nicholas; Hall, Alicia M; Roberson, Erik D (2014) The dendritic hypothesis for Alzheimer's disease pathophysiology. Brain Res Bull 103:18-28|
|Seward, Matthew E; Swanson, Eric; Norambuena, Andrés et al. (2013) Amyloid-? signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease. J Cell Sci 126:1278-86|
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