Chaperone imbalance drives tau pathogenesis: Molecular and cell biology/tau. (7th December 2020)

• Record Type: Journal Article
• Authors: Criado‐Marrero, Marangelie; Blair, Laura J.; Gebru, Niat; Blazier, Danielle; Baker, Jeremy D.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.045188
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The microtubule associated protein tau pathologically aggregates in neurons, a central component of ∼15 neurodegenerative diseases termed tauopathies, which include Alzheimer's and Parkinson's disease. Our work has demonstrated that age‐ and disease‐related changes to the cellular chaperone repertoire likely contribute to the abnormal buildup of tau. Recently, we have found that two Hsp90 co‐chaperones, the 52kDa FK506‐binding protein (FKBP52) and the activator of 90 kDa heat shock protein ATPase homolog 1 (Aha1), promote tau aggregation in vitro and in the brains of tau transgenic mice. This led us to hypothesize that imbalances in these chaperones may trigger tau misfolding in the aging brain. Method: To test this, we overexpressed Aha1, FKBP52, or control protein using adeno‐associated virus serotype 9 (AAV9) bilaterally injected into the hippocampus of 10‐month‐old wild‐type mice (n = 6/AAV). After 7 months of expression, we collected brain tissues to determine the effects on tau accumulation. Result: We have found that high levels of these chaperones can promote abnormal tau phosphorylation and aggregation, but that the species of tau that was affected was different depending on which chaperone what expressed. While we did see an overall increase in silver‐positive staining, we did not detect any true tau tangles in the brains of these mice. Conclusion: Based on these studies, we would expect that with enough time, or in the presence of human tau, high levels of these pro‐aggregation chaperones may be sufficient to drive tau pathogenesis. Overall, these findings demonstrate that imbalances in specific chaperones may have a significant impact on the tau in the aging brain.