The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus.
Accumulation of misfolded proteins in the endoplasmic reticulum triggers a cellular stress response called the unfolded protein response (UPR) that protects the cell against the toxic buildup of misfolded proteins. Previously, we reported that UPR activation is increased in Alzheimer's disease (AD) patients. How the UPR relates to the pathological hallmarks of AD is still elusive. In the present study, the involvement of UPR activation in neurofibrillary degeneration in AD was investigated. Immunoreactivity for the phosphorylated UPR activation markers pancreatic ER kinase (pPERK), eukaryotic initiation factor 2alpha, and inositol-requiring enzyme 1alpha was observed in hippocampal neurons associated with granulovacuolar degeneration. The percentage of pPERK-immunoreactive neurons was increased in AD cases compared with nondemented control cases and with the Braak stage for neurofibrillary changes. Although absent from neurofibrillary tangles, pPERK immunoreactivity was most abundant in neurons with diffuse localization of phosphorylated tau protein. Additional analyses showed that pPERK immunoreactivity was associated with ubiquitin and the ubiquitin binding protein p62. A strong co-occurrence of immunoreactivity for both pPERK and glycogen synthase kinase 3beta in neurons was also observed. Together, these data indicate that UPR activation in AD neurons occurs at an early stage of neurofibrillary degeneration and suggest that the prolonged activation of the UPR is involved in both tau phosphorylation and neurodegeneration in AD pathogenesis.
Hoozemans
Jeroen J M
JJ
VU University Medical Center, Department of Pathology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. jjm.hoozemans@vumc.nl
van Haastert
Elise S
ES
Nijholt
Diana A T
DA
Rozemuller
Annemieke J M
AJ
Eikelenboom
Piet
P
Scheper
Wiep
W
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D004722:Endoribonucleases / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004722:Endoribonucleases; D015852:Eukaryotic Initiation Factor-2; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin; D019892:eIF-2 Kinase; D016875:tau Proteins; C099718:SQSTM1 protein, human; C528229:ERN1 protein, human; C000605506:GSK3B protein, human