Article

Oligemic hypoperfusion differentially affects tau and amyloid-β

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.
American Journal Of Pathology (Impact Factor: 4.6). 07/2010; 177(1):300-10. DOI: 10.2353/ajpath.2010.090750
Source: PubMed

ABSTRACT 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.

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Available from: Kim N Green, May 28, 2014
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    • "Tau hyperphosphorylation and Ab overproduction appear to be very sensitive to cerebral hypoperfusion. Koike et al. have reported that a single, mild, cerebral hypoperfusion has profound and long lasting effects on tau hyperphosphorylation and Ab overproduction in 3xTg-AD mice (Koike et al. 2010). It is thus reasonable to speculate that repeated transient cerebral ischemia could contribute to the development of AD. "
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    • "so facilitate Ab production by activating the APP cleav - age enzyme b - secretase ( Kitaguchi et al . , 2009 ; Sun et al . , 2006 ; Tesco et al . , 2007 ; Wen et al . , 2004a ) . Cerebral ischemia promotes amyloid plaque formation ( Garcia - Alloza et al . , 2011 ; Kitaguchi et al . , 2009 ; Okamoto et al . , 2012 ) , and tau phos - phorylation ( Koike et al . , 2010 ; Wen et al . , 2007 ; 2004b ) . The vascular effects of Ab may also impair the clearance of the pep - tide , a key factor in brain Ab accumulation in sporadic AD ( Mawuenyega et al . , 2010 ) . The vascular pathway is estimated to be a major route of removal of Ab from the brain ( Castellano et al . , 2012 ; Shibata et al . , 2000 ) . "
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    • "The above mentioned and other studies suggest that cerebral hypoperfusion has the propensity to enhance APP, BACE 1, and Ab in the amyloid cascade, and promote the progression of cognitive decline (Kogure and Kato 1993; Koistinaho et al. 1996; Jendroska et al. 1997; Shi et al. 2000; de la Torre et al. 2003; Choi et al. 2011; Lee et al. 2011b; Zhiyou et al. 2009). Interestingly, let alone chronic, even a single, mild, transient episode of hypoperfusion acutely increased expression of b-secretase and Ab levels, and this effect was long lasting (Koike et al. 2010). In cerebrovascular hypoperfusion in adult rats, oligomeric Ab has an impact on hippocampus, synapses, and spatial memory, as a timedependent phenomenon (Wang et al. 2010). "
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