title: New developments in animal models of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by deterioration in mental function leading to dementia, deposition of amyloid plaques and neurofibrillary tangles (NFTs), and neuronal loss. The major component of plaques is the amyloid-beta peptide (A beta), whereas NFTs are assemblies of hyperphosphorylated forms of the microtubule-associated protein tau. Electron microscopy of NFTs reveals structures known as paired helical filaments (PHFs). In familial AD (FAD), mutations in three distinct genes drive A beta synthesis by favoring endoproteolytic secretase cleavages that liberate A beta from the Alzheimer beta-amyloid precursor protein (APP). This suggests that excess A beta initiates a pathogenic cascade in humans that culminates in all the pathologic and cellular hallmarks of AD. Building upon the knowledge of FAD mutations, incremental technical advances have now allowed reproduceable creation of APP transgenic mice that exhibit AD-like amyloid pathology and A beta burdens. These transgenic mouse lines also exhibit deficits in spatial reference and working memory, with immunization against A beta abrogating both AD-associated phenotypes. Besides establishing a proof of principle for A beta-directed therapies, these findings suggest a potential to identify individual elements in the pathogenic pathway that lead to cognitive dysfunction. Furthermore, transgenic APP mice with potent amyloid deposition will likely form a beach-head to capture the final elements of AD neuropathology--cell loss and NFTs composed of PHFs--that are missing from current transgenic models.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, University of Toronto, Tanz Neuroscience Building, 6 Queen's Park Crescent West, Toronto, Ontario M55 3H2, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Janus
authors.forename: A L
authors.initials: AL
authors.lastname: Phinney
authors.forename: M A
authors.initials: MA
authors.lastname: Chishti
authors.forename: D
authors.initials: D
authors.lastname: Westaway
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic