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 more than 15 neurodegenerative diseases collectively termed ?tauopathies?, the most common being Alzheimer?s disease and chronic traumatic encephalopathy (CTE). Here, we will investigate how small chaperone proteins impact these diseases by manipulating tau. These studies may lead to drug development that can provide sufferers of tauopathies a way to combat their condition, with the ultimate goal being a cure.

National Institute of Health (NIH)
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Neurobiology D (NURD)
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James A. Haley VA Medical Center
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Baker, Jeremy D; Shelton, Lindsey B; Zheng, Dali et al. (2017) Human cyclophilin 40 unravels neurotoxic amyloids. PLoS Biol 15:e2001336
Shelton, Lindsey B; Baker, Jeremy D; Zheng, Dali et al. (2017) Hsp90 activator Aha1 drives production of pathological tau aggregates. Proc Natl Acad Sci U S A 114:9707-9712
Martin, Mackenzie D; Baker, Jeremy D; Suntharalingam, Amirthaa et al. (2016) Inhibition of Both Hsp70 Activity and Tau Aggregation in Vitro Best Predicts Tau Lowering Activity of Small Molecules. ACS Chem Biol 11:2041-8
Fontaine, Sarah N; Zheng, Dali; Sabbagh, Jonathan J et al. (2016) DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins. EMBO J 35:1537-49
Sabbagh, Jonathan J; Fontaine, Sarah N; Shelton, Lindsey B et al. (2016) Noncontact Rotational Head Injury Produces Transient Cognitive Deficits but Lasting Neuropathological Changes. J Neurotrauma 33:1751-1760
Martin, Mackenzie D; Calcul, Laurent; Smith, Courtney et al. (2015) Synthesis, stereochemical analysis, and derivatization of myricanol provide new probes that promote autophagic tau clearance. ACS Chem Biol 10:1099-109
Blair, Laura J; Frauen, Haley D; Zhang, Bo et al. (2015) Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol Commun 3:8
Fontaine, Sarah N; Sabbagh, Jonathan J; Baker, Jeremy et al. (2015) Cellular factors modulating the mechanism of tau protein aggregation. Cell Mol Life Sci 72:1863-79
Fontaine, Sarah N; Martin, Mackenzie D; Akoury, Elias et al. (2015) The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics. Hum Mol Genet 24:3971-81
Fontaine, Sarah N; Rauch, Jennifer N; Nordhues, Bryce A et al. (2015) Isoform-selective Genetic Inhibition of Constitutive Cytosolic Hsp70 Activity Promotes Client Tau Degradation Using an Altered Co-chaperone Complement. J Biol Chem 290:13115-27

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