Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic mice
Accumulation of amyloid β peptides (Aβ) 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 Aβ elicits neuritic...
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| Format: | Article |
| Language: | English |
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Elsevier
2003-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999610300086X |
| _version_ | 1818675810884648960 |
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| author | Alyson L Peel Dale E Bredesen |
| author_facet | Alyson L Peel Dale E Bredesen |
| author_sort | Alyson L Peel |
| collection | DOAJ |
| description | Accumulation of amyloid β peptides (Aβ) 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 Aβ 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 Aβ 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. |
| first_indexed | 2024-12-17T08:33:30Z |
| format | Article |
| id | doaj.art-b9779c7fd72949caaddf38e8577c2a39 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T08:33:30Z |
| publishDate | 2003-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-b9779c7fd72949caaddf38e8577c2a392022-12-21T21:56:32ZengElsevierNeurobiology of Disease1095-953X2003-10-011415262Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic miceAlyson L Peel0Dale E Bredesen1Buck Institute for Age Research, Novato, CA, USABuck Institute for Age Research, Novato, CA, USAAccumulation of amyloid β peptides (Aβ) 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 Aβ 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 Aβ 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.http://www.sciencedirect.com/science/article/pii/S096999610300086XAlzheimer’s diseasePKRCell stress kinasePlaquesHistopathology |
| spellingShingle | Alyson L Peel Dale E Bredesen Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic mice Neurobiology of Disease Alzheimer’s disease PKR Cell stress kinase Plaques Histopathology |
| title | Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic mice |
| title_full | Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic mice |
| title_fullStr | Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic mice |
| title_full_unstemmed | Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic mice |
| title_short | Activation of the cell stress kinase PKR in Alzheimer’s disease and human amyloid precursor protein transgenic mice |
| title_sort | activation of the cell stress kinase pkr in alzheimer s disease and human amyloid precursor protein transgenic mice |
| topic | Alzheimer’s disease PKR Cell stress kinase Plaques Histopathology |
| url | http://www.sciencedirect.com/science/article/pii/S096999610300086X |
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