Published online before print March 5, 2009

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080814

Accepted for publication December 11, 2008.

Article

The Unfolded Protein Response Is Activated in Pretangle Neurons in Alzheimer's Disease Hippocampus

Jeroen J.M. Hoozemans^*@, Elise S. van Haastert^*, Diana A.T. Nijholt, Annemieke J.M. Rozemuller^*, Piet Eikelenboom, and Wiep Scheper

From the Department of Pathology,* VU University Medical Center, Amsterdam; the Neurogenetics Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; the Department of Psychiatry, VU University Medical Center, Amsterdam; and the Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

^@ To whom correspondence should be addressed. E-mail: jjm.hoozemans{at}vumc.nl.

	Abstract

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 2, and inositol-requiring enzyme 1 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 3 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.