title: Oligemic hypoperfusion differentially affects tau and amyloid-{beta}.
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.
authors.affiliation: 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.
authors.forename: Maya A
authors.initials: MA
authors.lastname: Koike
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
authors.forename: Frank M
authors.initials: FM
authors.lastname: Laferla
mesh_terms: 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*
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D016875:tau Proteins
references.citation: Stroke. 1992 Sep;23(9):1225-9
references.pmid: 1519275
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10966-71
references.pmid: 11526211
references.citation: Arch Neurol. 2003 Aug;60(8):1119-22
references.pmid: 12925369
references.citation: Ann N Y Acad Sci. 2008 Dec;1147:180-95
references.pmid: 19076441
references.citation: J Physiol. 2002 Jun 15;541(Pt 3):1013-23
references.pmid: 12068059
references.citation: Biochim Biophys Acta. 2007 Apr;1772(4):473-83
references.pmid: 17113760
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18727-32
references.pmid: 17121991
references.citation: Stroke. 1996 Aug;27(8):1283-9
references.pmid: 8711787
references.citation: Brain Res. 2004 Oct 1;1022(1-2):30-8
references.pmid: 15353210
references.citation: Neurobiol Aging. 2008 Nov;29(11):1607-18
references.pmid: 17544172
references.citation: EMBO J. 2000 Nov 1;19(21):5720-8
references.pmid: 11060023
references.citation: J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):654-7
references.pmid: 10519874
references.citation: Arch Neurol. 2000 Oct;57(10):1474-9
references.pmid: 11030800
references.citation: Acta Neuropathol. 1991;82(4):239-59
references.pmid: 1759558
references.citation: Neurosci Lett. 2000 Apr 28;284(3):187-9
references.pmid: 10773430
references.citation: J Neural Transm (Vienna). 2004 Apr;111(4):523-36
references.pmid: 15057522
references.citation: J Am Coll Cardiol. 2007 Jul 3;50(1):1-13
references.pmid: 17601538
references.citation: FASEB J. 2001 Aug;15(10):1837-9
references.pmid: 11481247
references.citation: Ann Neurol. 2007 Jul;62(1):59-66
references.pmid: 17503514
references.citation: J Cereb Blood Flow Metab. 2008 Feb;28(2):263-8
references.pmid: 17653130
references.citation: Int Psychogeriatr. 2003;15 Suppl 1:47-52
references.pmid: 16191216
references.citation: Neuron. 2007 Jun 7;54(5):721-37
references.pmid: 17553422
references.citation: Nature. 2002 Apr 4;416(6880):535-9
references.pmid: 11932745
references.citation: J Neurochem. 2001 May;77(3):953-6
references.pmid: 11331424
references.citation: Neuropathol Appl Neurobiol. 1991 Feb;17(1):69-74
references.pmid: 2057052
references.citation: Cell Motil Cytoskeleton. 2000 Nov;47(3):236-52
references.pmid: 11056524
references.citation: Eur J Biochem. 1998 Mar 15;252(3):542-52
references.pmid: 9546672
references.citation: J Biol Chem. 2007 Aug 17;282(33):24131-45
references.pmid: 17580304
references.citation: Neurobiol Dis. 2009 Feb;33(2):301-12
references.pmid: 19063968
references.citation: Neurobiol Aging. 2009 Jul;30(7):1091-8
references.pmid: 18063223
references.citation: Neurochem Res. 2006 Jun;31(6):821-7
references.pmid: 16794858
references.citation: N Engl J Med. 2003 Mar 27;348(13):1215-22
references.pmid: 12660385
references.citation: Acta Neurochir (Wien). 2001;143(3):287-95
references.pmid: 11460917
references.citation: Neurochem Res. 2009 Jul;34(7):1226-35
references.pmid: 19123057
references.citation: Science. 2003 Apr 18;300(5618):486-9
references.pmid: 12702875
references.citation: Eur J Neurosci. 2008 Mar;27(5):1119-30
references.pmid: 18294209
references.citation: J Am Geriatr Soc. 2004 Sep;52(9):1442-8
references.pmid: 15341544
references.citation: Neurobiol Aging. 2000 Mar-Apr;21(2):321-30
references.pmid: 10867217
references.citation: Arch Neurol. 2003 Dec;60(12):1707-12
references.pmid: 14676044
references.citation: Stroke. 2005 Jul;36(7):1551-6
references.pmid: 15933257
references.citation: Neurology. 1994 Oct;44(10):1885-91
references.pmid: 7936242
references.citation: Neurochem Res. 2007 Apr-May;32(4-5):729-37
references.pmid: 17191139
references.citation: Neuron. 2003 Jul 31;39(3):409-21
references.pmid: 12895417
references.citation: J Biol Chem. 2007 Apr 13;282(15):10873-80
references.pmid: 17303576
references.citation: Eur J Neurol. 2001 Nov;8(6):707-10
references.pmid: 11784357