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: 4.59). 07/2010; 177(1):300-10. DOI: 10.2353/ajpath.2010.090750
Source: PubMed


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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    • "Following transfer, the membranes were blocked overnight in PBS with 1% bovine serum albumin and 2% BlockAce (AbD Serotec, Raleigh, NC, USA). Blots were then probed with AT8 (Greco et al., 2010;Koike et al., 2010;van Eersel et al., 2010;MartinezCoria et al., 2010a) for pSer202/pThr205 tau (Pierce; 1:500), AT180 (Koike et al., 2010;Martinez-Coria et al., 2010a) for pThr231 tau (Pierce, 1:100), PHF-1 (Martinez-Coria et al., 2010a) for pSer396/pS404 (courtesy of Dr. Peter Davies, Albert Einstein College of Medicine , Bronx, NY 1:1000), HT7 (Koike et al., 2010;van Eersel et al., 2010;Martinez-Coria et al., 2010a) for total tau (Pierce, 1:1000) which has been shown to detect both human and rodent total tau (Oddo et al., 2007;Resende et al., 2008;Ke et al., 2009;Martinez-Coria et al., 2010b), and anti-GAPDH (ab9385, Abcam; Cambridge, MA, USA, 1:5000) antibodies then probed with HRP-conjugated rabbit anti-mouse secondary antibody (Rockland Immunochemicals; Gilbertsville, PA, USA, 1:10,000). Membranes were then incubated with SuperSignal West Dura chemiluminescent substrate (Pierce), and exposed to film. "
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