Abstract
The microtubule associated protein tau is an intrinsically disordered phosphoprotein that accumulates under pathological conditions leading to formation of neurofibrillary tangles, a hallmark of Alzheimer’s disease (AD). The mechanisms that initiate the accumulation of phospho-tau aggregates and filamentous deposits are largely unknown. In the past, our work and others’ have shown that molecular chaperones play a crucial role in maintaining protein homeostasis and that imbalance in their levels or activity can drive tau pathogenesis. We have found two co-chaperones of the 90 kDa heat shock protein (Hsp90), FK506-binding protein 52 (FKBP52) and the activator of Hsp90 ATPase homolog 1 (Aha1), promote tau aggregation in vitro and in the brains of tau transgenic mice. Based on this, we hypothesized that increased levels of these chaperones could promote tau misfolding and accumulation in the brains of aged wild-type mice. We tested this hypothesis by overexpressing Aha1, FKBP52, or mCherry (control) proteins in the hippocampus of 9-month-old wild-type mice. After 7 months of expression, mice were evaluated for cognitive and pathological changes. Our results show that FKBP52 overexpression impaired spatial reversal learning, while Aha1 overexpression impaired associative learning in aged wild-type mice. FKBP52 and Aha1 overexpression promoted phosphorylation of distinct AD-relevant tau species. Furthermore, FKBP52 activated gliosis and promoted neuronal loss leading to a reduction in hippocampal volume. Glial activation and phospho-tau accumulation were also detected in areas adjacent to the hippocampus, including the entorhinal cortex, suggesting that after initiation these pathologies can propagate through other brain regions. Overall, our findings suggest a role for chaperone imbalance in the initiation of tau accumulation in the aging brain.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in older adults [45]
Overexpression of activator of Hsp90 ATPase homolog 1 (Aha1) or FK506-binding protein 52 (FKBP52) did not significantly affect mobility (Fig. 2a) or anxiety levels (Fig. 2b), there was a trend toward an increase in anxiety-like behavior in Aha1 expressing mice when compared to control (#p = 0.07)
Because the accumulation of tau is critically linked with the progression of dementia in AD patients [4, 13, 32, 70, 72, 73, 77, 79, 89], we assessed whether high levels of Aha1 or FKBP52 affect associative fear and spatial learning in aged wild-type mice
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in older adults [45]. Criado‐Marrero et al acta neuropathol commun (2021) 9:65 transgenic mouse lines have been created that show tau accumulation, some with cognitive deficits and neuronal loss, which recapitulate aspects of the tauopathic brain [73, 82, 104] They have limitations often including the need to use tau mutations and/or overexpression [82, 104], which are not found in the AD brain. Mouse models have been created that express human tau at endogenous levels [3, 43, 44, 81], which are useful for studying age-related aspects of tauopathy While these models have some tau accumulation, they still do not capture the cascade of pathological events in the AD brain. Because of this many groups are potentiating the pathology in these models by injecting pathological tau seeds [21, 71], which is informative at understanding the propagation of tau through the brain but does not allow us to understand which events initiate tau accumulation under normal physiological conditions
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