The microtubule-associated protein tau is now thought to contribute to disease progression and pathogenesis in Alzheimer's disease both from within neurons and even between neurons via prion-like propagation. However, mechanisms that contribute to these pathogenic processes remain unclear. Here, we will fill these gaps in our knowledge by exploiting known anti-aggregant small chaperones that can function both inside and outside of neurons to distinctly regulate tau assembly and possibly toxicity. In fact, these small heat shock proteins are known to reside in the extracellular space and associate with both tau tangles and amyloid (A) plaques. We also know that small Hsps increase in the aging brain and even further in the Alzheimer's brain. Our team showed that a small heat shock protein blocks tau aggregation, reduces tau levels in vivo and restores hippocampal function in a tau transgenic mouse model; but a phosphorylated variant that has impaired activity may actually promote toxicity by producing more tau oligomers. We now have evidence that the other small Hsps can also prevent tau aggregation, and even just small peptidic cores of both these small Hsps are capable of blocking tau aggregation. With these tools, we can now test the hypothesis that tau toxicity arises due to structural changes in tau assemblies brought on by small Hsps that can function both inside and outside of the neuron. To test this, we will determine the impact of distinct small Hsp variants on tau oligomer formation and uptake. We will also determine the impact of intracellular small Hsps on functional deficits in a mouse model of tau proteotoxicity. And we will determine the impact of extracellular small Hsps on functional deficits and tau uptake in mouse and human models of tau proteotoxicity. Through these studies, we anticipate that we will identify ways to regulate tau aggregation using small Hsps, which will allow us to home in on structures of toxic tau intermediates. We also will determine whether distinct small Hsp variants can differentially triage aberrant tau from inside and outside of the neuron in the brain, possibly allowing us to improve the specificity of therapeutics targeting this mechanism.

Public Health Relevance

The tau protein accumulates in Alzheimer's disease and is thought to be critical for neuronal loss and brain damage in this devastating age-associated disease. Here, we will investigate how small chaperone proteins impact tau accumulation in Alzheimer's disease. These studies may lead to drug development that can provide sufferers of Alzheimer's a way to combat their condition, with the ultimate goal being a cure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG055088-01
Application #
9235345
Study Section
Special Emphasis Panel (ZRG1-MDCN-T (56)R)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$463,006
Indirect Cost
$153,303
Name
University of South Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612