Abstract
The unfolded protein response (UPR) in the endoplasmic reticulum (ER) and the cytoplasmic heat stress response are two major stress response systems necessary for maintaining proteostasis for cellular health. Failure of either of these systems, such as in sustained UPR activation or in insufficient heat shock response activation, can lead to the development of neurodegeneration. Alleviation of ER stress and enhancement of heat shock response through heat shock factor 1 (HSF1) activation have previously been considered as attractive potential therapeutic targets for Alzheimer’s disease (AD)—a prevalent and devastating tauopathy. Understanding the interplay of the two aforementioned systems and their cooperative role in AD remain elusive. Here we report studies in human brain and tau pathogenic mouse models (rTg4510, PS19, and rTg21221), identifying HSF1 degradation and UPR activation as precursors of aberrant tau pathogenesis. We demonstrate that chemical ER stress inducers caused autophagy-lysosomal HSF1 degradation, resulting in tau hyperphosphorylation in rat primary neurons. In addition, permanent HSF1 loss reversely causes chronic UPR activation, leading to aberrant tau phosphorylation and aggregation in the hippocampus of aged HSF1 heterozygous knock-out mice. The deleterious interplay of UPR activation and HSF1 loss is exacerbated in N2a cells stably overexpressing a pro-aggregation mutant TauRD ΔK280 (N2a-TauRD ΔK280). We provide evidence of how these two stress response systems are intrinsically interweaved by showing that the gene encoding C/EBP-homologous protein (CHOP) activation in the UPR apoptotic pathway facilitates HSF1 degradation, which likely further contributes to prolonged UPR via ER chaperone HSP70 a5 (BiP/GRP78) suppression. Upregulating HSF1 relieves the tau toxicity in N2a-TauRD ΔK280 by reducing CHOP and increasing HSP70 a5 (BiP/GRP78). Our work reveals how the bidirectional crosstalk between the two stress response systems promotes early tau pathology and identifies HSF1 being one likely key player in both systems.
Highlights
Neurofibrillary tangles (NFTs) of phosphorylated tau aggregates and senile plaques of amyloid beta (Aβ) are the pathological hallmarks of Alzheimer’s disease (AD) patients
This cellular protective system includes heat shock response regulated by heat shock factor 1 (HSF1) activation and unfolded protein response in endoplasmic reticulum (ER)
The current study reports how the interplay between the two stress response systems, unfolded protein response and HSF1 promotes early tau pathology and identifies HSF1 protein degradation being one likely key player in both human AD and tau transgenic mouse AD models
Summary
Neurofibrillary tangles (NFTs) of phosphorylated tau aggregates and senile plaques of amyloid beta (Aβ) are the pathological hallmarks of Alzheimer’s disease (AD) patients. NFTs exist primarily inside the cell, and has been associated with cellular stress responses [6, 7, 8] Such response systems include unfolded protein response (UPR) initiated in the endoplasmic reticulum (ER) and cytoplasmic heat shock response initiated by heat shock factor 1 (HSF1) activation. It is unknown whether and how ER stress causes tau phosphorylation, and vice versa While these two stress systems (i.e. heat shock response, UPR) have been originally considered to be individually triggered by distinct stressors, recent studies have begun to highlight the importance of heat shock responses in relieving ER stress in non-neuronal cells [11, 16, 17, 18]. How ER stress affects HSF1-mediated stress response is poorly understood, in the contexts of neurons and tauopathy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
