Reduction in Aha1 chaperone preserves hippocampal neurons and prevents tau‐related pathology in rTg4510 tau transgenic mice

Abstract

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.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.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.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.