Abstract
The endoplasmic reticulum (ER) stress response is regarded as an important process in the aetiology of Alzheimer's disease (AD). The accumulation of pathogenic misfolded proteins and the disruption of intracellular calcium (Ca2+) signalling are considered to be fundamental mechanisms that underlie the induction of ER stress, leading to neuronal cell death. Indeed, a number of studies have proposed molecular mechanisms linking ER stress to AD pathogenesis based on results from in vitro systems and AD mouse models. However, stress responsivity was largely different between each mouse model, even though all of these models display AD-related pathologies. While several reports have shown elevated ER stress responses in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) AD mouse models, we and other groups, in contrast, observed no such ER stress response in APP-single-Tg or App-knockin mice. Therefore, it is debatable whether the ER stress observed in APP and PS1 double-Tg mice is due to AD pathology. From these findings, the roles of ER stress in AD pathogenesis needs to be carefully addressed in future studies. In this review, we summarize research detailing the relationship between ER stress and AD, and analyse the results in detail.
Highlights
In 2015, approximately 47 million people were estimated to have dementia, and it is speculated that this population will increase to greater than 130 million by 2050 [1]
The 3XTg mouse exhibits elevated levels of GRP78, CHOP and p-eukaryotic translation initiation factor 2a subunit (eIF2a) compared to age-matched WT controls. These results indicate that the genetic modification of presenilin 1 (PS1), or double modifications of amyloid precursor protein (APP) and PS1, induced endoplasmic reticulum (ER) stress that is not related to the Alzheimer’s disease (AD) pathology
A number of studies have indicated the contribution of ER stress to the pathogenesis of AD
Summary
In 2015, approximately 47 million people were estimated to have dementia, and it is speculated that this population will increase to greater than 130 million by 2050 [1]. These disease-related mutations increase Ab levels or change the properties of Ab to more toxic forms. A number of reports have observed a cell-to-cell transfer of pathological tau protein in cultured cells and mouse models [24]. Such diffusion of pathological tau is considered to be a cause of neurodegeneration in tauopathy-related neurodegenerative diseases. The findings of studies on frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP17) suggested a direct interaction between tau pathology and neurodegeneration. As tau pathology appearing after amyloid pathology is well correlated with neurodegeneration in AD, the mechanism by which amyloid pathology is linked to tau pathology is considered to be one of the most important issues to be addressed [25]
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