A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model.
Senile plaques formed by β-amyloid peptides (Aβ) and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau, a microtubule-associated protein, are the hallmark lesions of Alzheimer's disease (AD) in addition to loss of neurons. While several transgenic (Tg) mouse models have recapitulated aspects of AD-like Aβ and tau pathologies, a spatiotemporal mapping paradigm for progressive NFT accumulation is urgently needed to stage disease progression in AD mouse models. Braak and co-workers developed an effective and widely used NFT staging paradigm for human AD brains. The creation of a Braak-like spatiotemporal staging scheme for tau pathology in mouse models would facilitate mechanistic studies of AD-like tau pathology. Such a scheme would also enhance the reproducibility of preclinical AD therapeutic studies. Thus, we developed a novel murine model of Aβ and tau pathologies and devised a spatiotemporal scheme to stage the emergence and accumulation of NFTs with advancing age. Notably, the development of NFTs followed a spatiotemporal Braak-like pattern similar to that observed in authentic AD. More significantly, the presence of Aβ accelerated NFT formation and enhanced tau amyloidosis; however, tau pathology did not have the same effect on Aβ pathology. This novel NFT staging scheme provides new insights into the mechanisms of tau pathobiology, and we speculate that this scheme will prove useful for other basic and translational studies of AD mouse models.
Hurtado
David E
DE
Department of Pathology, Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA.
Molina-Porcel
Laura
L
Iba
Michiyo
M
Aboagye
Awo K
AK
Paul
Steven M
SM
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins
J Neurosci. 1997 Sep 15;17(18):7053-9
9278541
Neurobiol Aging. 2003 Dec;24(8):1063-70
14643377
J Biol Chem. 2003 Feb 14;278(7):4458-66
12480937
Acta Neuropathol. 1991;82(4):239-59
1759558
Neurobiol Aging. 1989 Nov-Dec;10(6):709-15
2628782
Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1550-5
9037091
Ann Neurol. 1986 Oct;20(4):472-81
3789663
J Comp Neurol. 1976 Jun 1;167(3):285-314
1270625
J Biol Chem. 2006 Feb 17;281(7):4292-9
16361260
Neuron. 2007 Feb 1;53(3):337-51
17270732
Nature. 1995 Feb 9;373(6514):523-7
7845465
Ann N Y Acad Sci. 2000 Jun;911:1-24
10911864
Amyotroph Lateral Scler. 2008;9(1):4-15
18273714
Ann Neurol. 1997 Jan;41(1):17-24
9005861
Pharmacol Rev. 2002 Sep;54(3):469-525
12223532
J Neurosci Res. 1998 Jul 15;53(2):177-86
9671974
Science. 1984 Sep 14;225(4667):1168-70
6474172
Neurobiol Aging. 1995 May-Jun;16(3):271-8; discussion 278-84
7566337
Science. 2002 Jul 19;297(5580):353-6
12130773
Science. 1992 Apr 10;256(5054):184-5
1566067
Science. 2001 Aug 24;293(5534):1487-91
11520987
Science. 2001 Aug 24;293(5534):1491-5
11520988
Exp Neurol. 2000 May;163(1):98-110
10785448
Acta Neuropathol. 2006 Oct;112(4):389-404
16906426
Neurobiol Aging. 1997 Jul-Aug;18(4):351-7
9330961
J Alzheimers Dis. 2006;9(3 Suppl):35-44
16914843
Neuroscience. 2005;130(2):339-47
15664690
J Comp Neurol. 1972 Feb;144(2):215-32
4112908
Neurosci Lett. 1995 Apr 21;189(3):167-9
7624036
J Neuropathol Exp Neurol. 2006 Aug;65(8):740-57
16896308
Neurobiol Aging. 2004 Jul;25(6):697-711
15165691
Trends Genet. 2006 May;22(5):281-9
16567017
Neurobiol Dis. 2005 Dec;20(3):814-22
16125396
J Comp Neurol. 1976 Oct 1;169(3):347-70
972204
Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4837-42
12697936