Oligemic hypoperfusion differentially affects tau and amyloid-{beta}.
Decreased blood flow to the brain in humans is associated with altered Alzheimer's disease (AD)-related pathology, although the underlying mechanisms by which hypoperfusion influences AD neuropathology remains unknown. To try to address this question, we developed an oligemic model of cerebral hypoperfusion in the 3xTg-AD mouse model of AD. We bilaterally and transiently occluded the common carotid artery and then examined the molecular and cellular pathways by which hypoperfusion influenced tau and amyloid-beta proteins. We report the novel finding that a single, mild, transient hypoperfusion insult acutely increases Abeta levels by enhancing beta-secretase protein expression. In contrast, transient hypoperfusion markedly decreases total tau levels, coincident with activation of macroautophagy and ubiquitin-proteosome pathways. Furthermore, we find that oligemia results in a significant increase specifically in tau phosphorylated at serine(212) and threonine(214), a tau epitope associated with paired helical filaments in AD patients. Despite the mild and transient nature of this hypoperfusion injury, the pattern of decreased total tau, altered phosphorylated tau, and increased amyloid-beta persisted for several weeks postoligemia. Our study indicates that a single, mild, cerebral hypoperfusion event produces profound and long lasting effects on both tau and amyloid-beta. This finding may have implications for the pathogenesis of AD, as it indicates for the first time that total tau and amyloid-beta are differentially impacted by mild hypoperfusion.
Koike
Maya A
MA
Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 3212 Biological Sciences III, Irvine, CA 92697-4545, USA.
Green
Kim N
KN
Blurton-Jones
Mathew
M
Laferla
Frank M
FM
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism* / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012039:Regional Blood Flow / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D016875:tau Proteins
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