Abstract
Alzheimer's disease (AD) is the first most common neurodegenerative disease. Despite a large amount of research, the pathogenetic mechanism of AD has not yet been clarified. The two hallmarks of the pathology of AD are the extracellular senile plaques (SPs) of aggregated amyloid-beta (Aβ) peptide and the accumulation of the intracellular microtubule-associated protein tau into fibrillar aggregates. Heat shock proteins (HSPs) play a key role in preventing protein misfolding and aggregation, and Hsp90 can be viewed as a ubiquitous molecular chaperone potentially involved in AD pathogenesis. A role of Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1), the master regulator of the heat shock response. In AD, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70. Therefore, we review here to further discuss the recent advances and challenges in targeting Hsp90 for AD therapy.
Highlights
Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder that is characterized by the formation of extracellular accumulation of amyloid-β (Aβ) in senile plaques and intracellular neurofibrillary tangles (NFTs) [1]
heat shock proteins (HSPs) as molecular chaperones play an important role in the quality control of proteins, and Heat shock protein 90 (Hsp90) is involved in the folding, activation, and assembly of its client proteins as a ubiquitous molecular chaperone
It has been proved that Hsp90 might become a potential therapeutic target for AD
Summary
Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder that is characterized by the formation of extracellular accumulation of amyloid-β (Aβ) in senile plaques and intracellular neurofibrillary tangles (NFTs) [1]. Heat shock protein 90 (Hsp90), as a molecular chaperone, is capable of suppressing protein aggregation, solubilizing protein aggregates, and targeting protein clients for degradation. Kakimura et al found that extracellular heat shock proteins (HSPs), such as Hsp, Hsp, and Hsp, may facilitate Aβ clearance by the activation of microglial phagocytosis and Aβ degradation by NF-κB and p38 MAPK activation through the Toll-like receptor-4 (TLR4) pathway [4]. Cochaperones were involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp refolding complex prevented this effect. It may provide a rationale for the development of novel Hsp90-based therapeutic strategies [5]. We review the recent knowledge on Hsp in AD and will focus on the potential advances and challenges in targeting Hsp for AD therapy
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