FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model

Abstract

Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer’s disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.

With or Without You: Co-chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

“…Contrary to this observation, FKBP52 overexpression in rTg4510 mice failed to show an increase in phosphorylated tau species [237]. However, they observed a decline in spatial learning and increased neuronal loss in the hippocampus of rTg4510 mice overexpressing FKBP52, further highlighting the beneficial effects of FKBP52 inhibition in AD [237].…”

“…Interestingly, the interactions between FKBP52 and different tau species are independent of FKBP52's PPIase activity [235]. New studies investigated the role of FKBP52 in tau pathology and tau-mediated cognitive deficits in wild-type and tau transgenic mouse models [236,237]. FKBP52 overexpression in aged wild-type mice resulted in increased phosphorylation of AD-associated tau species and impairments in spatial reversal learning [236].…”

Non-Rodent Genetic Animal Models for Studying Tauopathy: Review of Drosophila, Zebrafish, and C. elegans Models

“…Negative-charged polyanions, such as glycosaminoglycans, and their sulfated forms (e.g., heparin) or RNA (e.g., polyU RNA) can promote Tau aggregation in vitro [45][46][47][48]. Another cofactor, FKBP52 (the 52 kD FK506-binding protein), also induces Tau aggregation in vitro and accelerates memory impairments in vivo [49,50].…”

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

“…Interestingly, the interactions between FKBP52 and different tau species are independent of FKBP52's PPIase activity [257]. New studies investigated the role of FKBP52 in tau pathology and tau-mediated cognitive deficits in wild-type and tau transgenic mouse models [258,259]. FKBP52 overexpression in aged wild-type mice resulted in increased phosphorylation of AD-associated tau species and impairments in spatial reversal learning [258].…”