title: Stress acts cumulatively to precipitate Alzheimer's disease-like tau pathology and cognitive deficits.
abstract: Stressful life experiences are likely etiological factors in sporadic forms of Alzheimer's disease (AD). Many AD patients hypersecrete glucocorticoids (GCs), and their GC levels correlate with the rate of cognitive impairment and extent of neuronal atrophy. Severity of cognitive deficits in AD correlates strongly with levels of hyperphosphorylated forms of the cytoskeletal protein TAU, an essential mediator of the actions of amyloid β (Aβ), another molecule with a key pathogenic role in AD. Our objective was to investigate the sequential interrelationships between these various pathogenic elements, in particular with respect to the mechanisms through which stress might precipitate cognitive decline. We thus examined whether stress, through the mediation of GCs, influences TAU hyperphosphorylation, a critical and early event in the cascade of processes leading to AD pathology. Results from healthy, wild-type, middle-aged rats show that chronic stress and GC induce abnormal hyperphosphorylation of TAU in the hippocampus and prefrontal cortex (PFC), with contemporaneous impairments of hippocampus- and PFC-dependent behaviors. Exogenous GC potentiated the ability of centrally infused Aβ to induce hyperphosphorylation of TAU epitopes associated with AD and cytoplasmic accumulation of TAU, while previous exposure to stress aggravated the biochemical and behavioral effects of GC in Aβ-infused animals. Thus, lifetime stress/GC exposure may have a cumulative impact on the onset and progress of AD pathology, with TAU hyperphosphorylation serving to transduce the negative effects of stress and GC on cognition.
authors: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors: Ioannis
authors: I
authors: Sotiropoulos
authors: Caterina
authors: C
authors: Catania
authors: Lucilia G
authors: LG
authors: Pinto
authors: Rui
authors: R
authors: Silva
authors: G Elizabeth
authors: GE
authors: Pollerberg
authors: Akihiko
authors: A
authors: Takashima
authors: Nuno
authors: N
authors: Sousa
authors: Osborne F X
authors: OF
authors: Almeida
references: FASEB J. 2006 Apr;20(6):729-31
references: 16467370
references: J Biol Chem. 1995 Mar 3;270(9):4854-60
references: 7876258
references: Dementia. 1996 Jul-Aug;7(4):177-81
references: 8835879
references: Am J Psychiatry. 2006 Dec;163(12):2164-9
references: 17151169
references: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6058-63
references: 20231476
references: Neurosci Res. 2006 Mar;54(3):197-201
references: 16406150
references: Curr Alzheimer Res. 2007 Apr;4(2):205-12
references: 17430248
references: J Psychiatr Res. 2008 Sep;42(11):902-12
references: 18177670
references: J Neurosci. 2007 Apr 4;27(14):3650-62
references: 17409229
references: Cell. 2010 Aug 6;142(3):387-97
references: 20655099
references: J Neuropathol Exp Neurol. 2002 May;61(5):384-95
references: 12025941
references: Neurosci Res. 1998 Aug;31(4):317-23
references: 9809590
references: Arch Biochem Biophys. 1998 Sep 15;357(2):299-309
references: 9735171
references: Neurosci Biobehav Rev. 2008 Aug;32(6):1161-73
references: 18573532
references: Ann Neurol. 1991 Oct;30(4):572-80
references: 1789684
references: Arch Neurol. 2003 May;60(5):729-36
references: 12756137
references: Neuron. 2010 Dec 22;68(6):1067-81
references: 21172610
references: J Neurosci. 2007 Mar 14;27(11):2781-7
references: 17360899
references: Biochemistry. 1999 Mar 23;38(12):3549-58
references: 10090741
references: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18367-72
references: 19837693
references: Eur J Neurosci. 2007 Jan;25(1):59-68
references: 17241267
references: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6923-8
references: 11381127
references: Neuroscience. 2000;97(2):253-66
references: 10799757
references: Biol Psychiatry. 2006 Jan 15;59(2):155-61
references: 16125145
references: Arch Neurol. 2005 May;62(5):770-3
references: 15883264
references: J Neurosci. 2006 Aug 30;26(35):9047-56
references: 16943563
references: J Neurochem. 2008 Oct;107(2):385-97
references: 18691381
references: Biol Psychiatry. 1997 Dec 1;42(11):1030-8
references: 9386855
references: Neurobiol Aging. 1997 May-Jun;18(3):285-9
references: 9263193
references: Neurology. 2009 Mar 24;72(12):1056-61
references: 19307538
references: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10673-8
references: 17551018
references: Nat Rev Drug Discov. 2007 Jun;6(6):464-79
references: 17541419
references: Mol Psychiatry. 2009 Jan;14(1):95-105
references: 17912249
references: Arch Gen Psychiatry. 2008 May;65(5):542-50
references: 18458206
references: Chem Biol. 1997 Feb;4(2):119-25
references: 9190286
references: J Biol Chem. 2010 Dec 3;285(49):38692-9
references: 20921222
references: EMBO J. 2007 Dec 12;26(24):5143-52
references: 18007595
references: Int Psychogeriatr. 1998 Mar;10(1):85-96
references: 9629527
references: Neurology. 2007 Jun 12;68(24):2085-92
references: 17562829
references: Nat Rev Neurosci. 2009 Jun;10(6):434-45
references: 19401723
references: J Neurosci. 1994 Sep;14(9):5373-80
references: 8083742
references: Neurobiol Aging. 2003 Oct;24(6):767-76
references: 12927759
references: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8864-9
references: 16735465
references: Genes Brain Behav. 2005 Apr;4(3):157-72
references: 15810904
references: Neurology. 2007 Dec 11;69(24):2205-12
references: 18071141
references: J Neurosci. 1991 May;11(5):1478-84
references: 1674004
references: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6364-9
references: 11959919
references: Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913-7
references: 3088567
references: Prog Neurobiol. 2010 Apr;90(4):498-510
references: 20097254
references: Eur J Neurosci. 2006 Dec;24(12):3354-64
references: 17229084
references: J Neurosci. 2007 Jun 13;27(24):6552-62
references: 17567816
references: J Neurosci. 2011 Feb 2;31(5):1688-92
references: 21289177
references: Neuron. 1995 Apr;14(4):879-88
references: 7718249
references: Science. 2007 May 4;316(5825):750-4
references: 17478722
references: Arch Gen Psychiatry. 2006 May;63(5):530-8
references: 16651510
references: Brain. 2009 May;132(Pt 5):1324-34
references: 19321462
references: Neurology. 2003 Dec 9;61(11):1479-85
references: 14663028
references: Arch Gen Psychiatry. 2006 Feb;63(2):168-74
references: 16461860
references: Acta Neuropathol. 2002 Jan;103(1):26-35
references: 11837744