Summary: A new preclinical study has identified the role chaperone protein imbalance plays in initiating the accumulation of tau in the brain.
Chaperone protein imbalance can play a significant role in initiating toxic accumulation of tau in the aging brain – an early step in the development of Alzheimer’s disease and related neurodegenerative disorders known as tauopathies, a new preclinical study by University of South Florida Health (USF Health) neuroscientists suggests.
In humans, misfolding of the protein tau leads to its toxic accumulation inside brain cells, the formation of these tau aggregates into hallmark neurofibrillary tangles, neuron death, and eventually symptoms of cognitive decline such as memory loss and diminished thinking skills.
In this study the USF Health Morsani College of Medicine researchers used mice that were not genetically modified (wild-type mice) to examine the effects of Aha1 and FKBP52, two co-chaperone proteins of heat shock protein Hsp90, in the aging brain. They modeled molecular chaperone imbalance by overexpressing production of Aha1 and FKBP52 in these old, wide-type mice. The findings, highlighted below, were reported April 8 in Acta Neuropathologica Communications.
Hsp90 is a chaperone protein abundant in neurons and other cells in the brain. Normally, co-chaperone proteins assist chaperone proteins in monitoring and sustaining the balance (homeostasis) of proteins critical to cell health.
“The chaperone protein network is your cell’s natural defense to maintain homeostasis throughout life, and this study emphasizes the importance of protecting that balance in the aging brain,” said principal investigator Laura Blair, PhD, an assistant professor of molecular medicine at the USF Health Byrd Alzheimer’s Center, Morsani College of Medicine. “We’re excited about using this new model of tauopathy in finding ways to restore chaperone protein balance to delay or stop the progression of Alzheimer’s and other neurodegenerative diseases.”
Among their many quality-control functions, chaperone protein networks ensure proteins are folded to conform to the proper 3D shapes, transported precisely where needed to do their jobs, and pushed toward degradation if they are abnormally modified or no longer useful. Heat shock proteins like Hsp90, triggered when a cell is under stress, play a particularly important “triage” role in correcting protein misfolding to prevent aggregation.
“But in the aging brain, the balance of the chaperone proteins shifts and creates a system not working as efficiently as it normally would. Large numbers of the chaperone molecules decrease in expression, and a smaller but significant number increase in their expression,” Dr. Blair said.
Increasing age is the greatest known risk factor for Alzheimer’s disease. So, the USF Health team investigated whether increased levels of FKBP52 and Aha1 alone could initiate pathological features mimicking human Alzheimer’s disease in aged wild-type mice – those with no genetic manipulations predisposing their brains to abnormally increase tau aggregation.
Key findings from their new mouse model of tauopathy include:
High levels of FKBP52, and to a lesser extent elevated levels of Aha1, increased tau accumulation over time in the aged, wild-type mice.
The tau accumulation promoted by overexpression of FKBP52, but not Aha1, correlated with increased neuroinflammation through exaggerated activation of neuronal support cells, namely microglia and astrocytes. This was complemented by loss of neurons and cognitive impairments.
Existing mouse models, including those that add or subtract genes, introduce tau mutations, and seed mice brains with human tau, help scientists learn more about the underlying causes of Alzheimer’s disease and other tauopathies. However, they tend to be limited in capturing the physiological aspects of neurodegeneration in the context of both normal and abnormal aging.
“We hope this (chaperone imbalance) model will help us better understand the dynamics of tau aggregation and neuroinflammation, including the timing and connections among pathological events, without directly regulating one pathway or the other,” Dr. Blair said.
Dr. Blair’s team has designed follow-up studies to help unravel if, and when, tau accumulation or neuroinflammation is more influential in causing brain cell toxicity during aging. That could help determine which chaperones — FKBP52, Aha1, or others — may be the best therapeutic target options for restoring protein balance, she said.
Co-lead authors for the USF Health study were postdoctoral fellow Marangelie Criado-Marrero, PhD, and doctoral student Niat Gebru.
Funding: The research was supported by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health.
About this neurology research news
Source: USF Contact: Anne DeLotto DeLotto Baier – USF Image: The image is credited to Laura Blair’s laboratory, USF Health/University of South Florida
Hsp90 co-chaperones, FKBP52 and Aha1, promote tau pathogenesis in aged wild-type mice
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.