Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

Abstract

Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5 -/-mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

The role of protein clearance mechanisms in organismal ageing and age-related diseases

“…In vitro, the proteasome activator Blm10 accelerates degradation of unstructured tau 95 . Tau clearance is blocked by FK506 binding protein 51 kDa (FKBP51), which forms a chaperone complex with Hsp90 that prevents tau degradation resulting in tau oligomerization 96 . In humans, FKBP51 levels increase with age and higher FKBP51 levels are associated with AD progression 96 .…”

Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds

“…When brain-derived tau oligomers are administered to wild-type (WT) mice, they induce both synaptic and mitochondrial toxicity [25]. Overexpression of a chaperone inducing tau oligomerization causes neuronal toxicity in mice [26]. Furthermore, there is evidence that tau oligomers seed the misfolding of endogenous tau [27] and are responsible for the spread of tau pathology from affected regions in the brain to unaffected areas [28].…”

MicroRNA-511 Binds to FKBP5 mRNA, Which Encodes a Chaperone Protein, and Regulates Neuronal Differentiation

“…Previous studies have demonstrated that FKBP5 expression increases with age in humans (11). To determine whether murine Fkbp5 expression aligned with these previous findings and to investigate expression of miR-511 with age, RT-PCR was employed to determine mRNA levels in the hippocampus of WT mice at various ages (Fig.…”

“…The current study identified and confirmed miR-511 as a regulator of FKBP5, a gene associated with risk for stress-related disorders including major depression and PTSD. FKBP51 has also been linked to AD, with elevated levels observed in AD brains (11). FKBP51 accelerates formation of Tau oligomers and enhances neurotoxicity in a mouse model of AD, suggesting that its inhibition would be beneficial.…”

“…FKBP51 expression is also increased in Alzheimer disease (AD), which is characterized by accumulation of misfolded Tau (10). FKBP51 has been shown to accelerate Tau oligomerization and neurotoxicity in vitro and in vivo, suggesting that it may be contributing to the pathogenesis of AD (11). Therefore, reducing FKBP51 expression is of significant interest in both depression and AD; however, little is known about what genetically regulates FKBP5, aside from its glucocorticoid response element (GRE) responsiveness (12).…”