Induction of neuronal death by ER stress in Alzheimer's disease.
Recent studies have suggested that neuronal death in Alzheimer's disease (AD) or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Inhibition of protein glycosylation, perturbation of calcium homeostasis, and reduction of disulfide bonds provoke accumulation of unfolded protein in the ER, and are called 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, to facilitate protein folding or by suppressing the mRNA translation to synthesize proteins. These systems are termed the unfolded protein response (UPR). Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6. On the other hand, in sporadic Alzheimer's disease (sAD), we found the aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, responsible for induction of high mobility group A1a protein (HMGA1a). The PS2V also downregulates the signaling pathway of the UPR, in a similar fashion to that reported for mutants of PS1 linked to familial AD. It was clarified what molecules related to cell death are activated in the case of AD and we discovered that caspase-4 plays a key role in ER stress-induced apoptosis. Caspase-4 also seems to act upstream of the beta-amyloid-induced ER stress pathway, suggesting that activation of caspase-4 might mediate neuronal cell death in AD.
Katayama
Taiichi
T
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka, University, Suita, Osaka 565-0871, Japan. katayama@anat2.med.osaka-u.ac.jp
Imaizumi
Kazunori
K
Manabe
Takayuki
T
Hitomi
Junichi
J
Kudo
Takashi
T
Tohyama
Masaya
M
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016923:Cell Death / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology