Activation of the cell stress kinase PKR in Alzheimer's disease and human amyloid precursor protein transgenic mice.
Accumulation of amyloid beta peptides (Abeta) in the brain, which is a hallmark of Alzheimer's disease (AD), is associated with progressive damage to neuronal processes resulting in extensive neuritic dystrophy. This process may contribute to cognitive decline, but it is not known how Abeta elicits neuritic injury. Our analysis of AD brains and related transgenic mouse models suggests an involvement of the interferon-induced serine-threonine protein kinase, PKR, which is best known for its activation upon binding to double-stranded RNA. PKR activation is a component of stress-activated pathways that mobilize somatic cell death programs, but its roles in neurological disease largely remain to be defined. An antibody specific to the activated form of PKR (phosphorylated at T451) was used to determine the pattern of PKR activation in postmortem brain tissues from humans or from transgenic mice that express high levels of familial AD-mutant human amyloid precursor protein (hAPP) and hAPP-derived Abeta in neurons. In contrast to nondemented controls, AD cases showed prominent granular phospho-PKR immunoreactivity in association with neuritic plaques and pyramidal neurons in the hippocampus and neocortex. The distribution of phospho-PKR matched the distributions of abnormally phosphorylated tau and active p38 MAP kinase in adjacent sections. Compared with nontransgenic controls, hAPP transgenic mice also showed strong increases in phospho-PKR in the brain, primarily in association with plaques and dystrophic neurites. These findings support a role for PKR activation in the pathogenesis of AD.
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D019892:eIF-2 Kinase / Q000096:biosynthesis* / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D019892:eIF-2 Kinase