Biochemical and Morphological Characterization of the AβPP/PS/Tau Triple Transgenic Mouse Model and Its Relevance to Sporadic Alzheimer's Disease

Article type: Research Article

Authors: Hunter, Jesse M.^a | Bowers, William J.^b | Maarouf, Chera L.^a | Mastrangelo, Michael A.^b | Daugs, Ian D.^a | Kokjohn, Tyler A.^{a; c} | Kalback, Walter M.^a | Luehrs, Dean C.^a | Valla, Jon^d | Beach, Thomas G.^e | Roher, Alex E.^{a; *}

Affiliations: [a] The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, Sun City, AZ, USA | [b] Department of Neurology, Center for Neural Development and Disease, University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA | [c] Department of Microbiology, Midwestern University, Glendale, AZ, USA | [d] Department of Biochemistry, Midwestern University, Glendale AZ, USA | [e] Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA

Correspondence: [*] Correspondence to: Alex E. Roher, M.D., Ph.D., Senior Scientist and Director, Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, 10515 W. Santa Fe Dr. Sun City, AZ 85351, USA. Tel.: 623 876 5465; Fax: 623 876 5698; E-mail: alex.roher@bannerhealh.com.

Abstract: Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been genetically altered with human familial AD genes driven by powerful promoters. However, a Tg model must accurately mirror the pathogenesis of the human disease, not merely the signature amyloid and/or tau pathology, as such hallmarks can arise via multiple convergent or even by pathogenic mechanisms unrelated to human sporadic AD. The 3 × Tg-AD mouse simultaneously expresses 3 rare familial mutant genes that in humans independently produce devastating amyloid-β protein precursor (AβPP), presenilin-1, and frontotemporal dementias; hence, technically speaking, these mice are not a model of sporadic AD, but are informative in assessing co-evolving amyloid and tau pathologies. While end-stage amyloid and tau pathologies in 3 × Tg-AD mice are similar to those observed in sporadic AD, the pathophysiological mechanisms leading to these lesions are quite different. Comprehensive biochemical and morphological characterizations are important to gauge the predictive value of Tg mice. Investigation of AβPP, amyloid-β (Aβ), and tau in the 3 × Tg-AD model demonstrates AD-like pathology with some key differences compared to human sporadic AD. The biochemical dissection of AβPP reveals different cleavage patterns of the C-terminus of AβPP when compared to human AD, suggesting divergent pathogenic mechanisms. Human tau is concomitantly expressed with AβPP/Aβ from an early age while abundant extracellular amyloid plaques and paired helical filaments are manifested from 18 months on. Understanding the strengths and limitations of Tg mouse AD models through rigorous biochemical, pathological, and functional analyses will facilitate the derivation of models that better approximate human sporadic AD.

Keywords: Alzheimer's disease, amyloid-β precursor protein, presenilin, tau, transgenic mice

DOI: 10.3233/JAD-2011-110608

Journal: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 361-376, 2011