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New developments in animal models of Alzheimer’s disease

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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-b peptide (Ab), 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 Aβ synthesis by favoring endoproteolytic secretase cleavages that liberate Aβ from the Alzheimer b-amyloid precursor protein (APP). This suggests that excess Ab 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 Aβ burdens. These transgenic mouse lines also exhibit deficits in spatial reference and working memory, with immunization against Aβ abrogating both AD-associated phenotypes. Besides establishing a proof of principle for Ab-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 beachhead to capture the final elements of AD neuropathology—cell loss and NFTs composed of PHFs—that are missing from current transgenic models.

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Authors and Affiliations

  1. Centre for Research in Neurodegenerative Diseases, University of Toronto, Tanz Neuroscience Building, 6 Queen’s Park Crescent West, M5S 3H2, Toronto, Ontario, Canada

    Christopher Janus PhD, Amie L. Phinney PhD, M. Azhar Chishti PhD & David Westaway PhD

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  1. Christopher Janus PhD
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  2. Amie L. Phinney PhD
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  3. M. Azhar Chishti PhD
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  4. David Westaway PhD
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Janus, C., Phinney, A.L., Chishti, M.A. et al. New developments in animal models of Alzheimer’s disease. Curr Neurol Neurosci Rep 1, 451–457 (2001). https://doi.org/10.1007/s11910-001-0105-8

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  • DOI: https://doi.org/10.1007/s11910-001-0105-8

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