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The ATP-dependent 90 kDa heat shock protein, Hsp90, is a major regulator of protein triage, from assisting in nascent protein folding to refolding or degrading aberrant proteins. Tau, a microtubule associated protein, aberrantly accumulates in Alzheimer's disease (AD) and other neurodegenerative diseases, deemed tauopathies. Hsp90 binds to and regulates tau fate in coordination with a diverse group of co-chaperones. Imbalances in chaperone levels and activity, as found in the aging brain, can contribute to disease onset and progression. For example, the levels of the Hsp90 co-chaperone, FK506-binding protein 51 kDa (FKBP51), progressively increase with age. In vitro and in vivo tau models demonstrated that FKBP51 synergizes with Hsp90 to increase neurotoxic tau oligomer production. Inversely, protein phosphatase 5 (PP5), which dephosphorylates tau to restore microtubule-binding function, is repressed with aging and activity is further repressed in AD. Similarly, levels of cyclophilin 40 (CyP40) are reduced in the aged brain and further repressed in AD. Interestingly, CyP40 was shown to breakup tau aggregates in vitro and prevent tau-induced neurotoxicity in vivo. Moreover, the only known stimulator of Hsp90 ATPase activity, Aha1, increases tau aggregation and toxicity. While the levels of Aha1 are not significantly altered with aging, increased levels have been found in AD brains. Overall, these changes in the Hsp90 heterocomplex could drive tau deposition and neurotoxicity. While the relationship of tau and Hsp90 in coordination with these co-chaperones is still under investigation, it is clear that imbalances in these proteins with aging can contribute to disease onset and progression. This review highlights the current understanding of how the Hsp90 family of molecular chaperones regulates tau or other misfolded proteins in neurodegenerative diseases with a particular emphasis on the impact of aging. [ABSTRACT FROM AUTHOR]

The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer’s disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids. [ABSTRACT FROM AUTHOR]

Background: Several molecular chaperones have been identified as important modulators of tau protein in aging and neurodegenerative illnesses like Alzheimer's diseases. Tau‐related diseases, collectively known as tauopathies, are characterized by abnormal deposition of insoluble tau protein leading to neuronal degeneration and the formation of neurofibrillary tangles in the brain. Although the exact mechanism is largely unknown, discrete molecular chaperones are known to regulate tau stability. Our laboratory demonstrated the activator of Hsp90 ATPase Activity (Aha1) potently promotes tau fibrilization and its expression positively correlates with features of tau pathology in brains from tau overexpressing mice and individuals with Alzheimer's disease. In this study, we investigate whether reduction of Aha1 levels in tau transgenic mice is sufficient to slow the progression of tau pathology in brains of rTg4510 tau transgenic mice. Method: To test this, we designed three AAV9 plasmids targeting Aha1 and a scramble shRNA was used as control. Aha1 knockdown was confirmed in N2A cells using Western blot analysis. Following this, 4‐month‐old rTg4510 male and female tau transgenic mice were injected into the hippocampus with Aha1‐shRNA or scramble‐shRNA (control). Two months were allowed for viral expression followed by the collection of brains for protein and tissue analysis. Result: n N2A cells, one out of three Aha1‐targeting shRNAs effectively reduced Aha1 expression after 72 hours of viral transfection. In animals, Aha1 knockdown decreased pS396/404 and AT8 phosphorylated tau as well Gallyas‐silver positive tau tangles in the hippocampus. Total or oligomeric tau were not affected in mice injected with AAV9‐shAha1 when compared to AAV9‐scramble animals. Using unbiased stereology, we found that hippocampal CA1 neurons were preserved after reducing Aha1. Conclusion: Our findings demonstrate that Aha1 knockdown reduces tau phosphorylated species, prevents tau tangle formation, and rescued CA1 hippocampal neurons in rTg4510 mice. Overall, these in vivo observations suggest that Aha1 knockdown could prevent development of pathological features like tangle formation in tauopathies. Although further examinations in human brain are needed, Aha1 inhibition could be a potential therapeutic target to slow or prevent tau pathologies. [ABSTRACT FROM AUTHOR]

Three scaffolds with inhibitory activity against the heat shock protein 70 (Hsp70) family of chaperones have been found to enhance the degradation of the microtubule associated protein tau in cells, neurons, and brain tissue. This is important because tau accumulation is linked to neurodegenerative diseases including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Here, we expanded upon this study to investigate the anti-tau efficacy of additional scaffolds with Hsp70 inhibitory activity. Five of the nine scaffolds tested lowered tau levels, with the rhodacyanine and phenothiazine scaffolds exhibiting the highest potency as previously described. Because phenothiazines also inhibit tau aggregation in vitro, we suspected that this activity might be a more accurate predictor of tau lowering. Interestingly, the rhodacyanines did inhibit in vitro tau aggregation to a similar degree as phenothiazines, correlating well with tau-lowering efficacy in cells and ex vivo slices. Moreover, other Hsp70 inhibitor scaffolds with weaker tau-lowering activity in cells inhibited tau aggregation in vitro, albeit at lower potencies. When we tested six well-characterized tau aggregation inhibitors, we determined that this mechanism of action was not a better predictor of tau-lowering than Hsp70 inhibition. Instead, we found that compounds possessing both activities were the most effective at promoting tau clearance. Moreover, cytotoxicity and PAINS activity are critical factors that can lead to false-positive lead identification. Strategies designed around these principles will likely yield more efficacious tau-lowering compounds.