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Presenilin transgenic mice as models of Alzheimer’s disease

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Abstract

Mutations in presenilin-1 (PS1) and presenilin-2 (PS2) cause familial Alzheimer’s disease (FAD). Presenilins influence multiple molecular pathways and are best known for their role in the γ-secretase cleavage of type I transmembrane proteins including the amyloid precursor protein (APP). PS1 and PS2 FAD mutant transgenic mice have been generated using a variety of promoters. PS1-associated FAD mutations have also been knocked into the endogenous mouse gene. PS FAD mutant mice consistently show elevations of Aβ42 with little if any effect on Aβ40. When crossed with plaque forming APP FAD mutant lines, the PS1 FAD mutants cause earlier and more extensive plaque deposition. Although single transgenic PS1 or PS2 mice do not form plaques, they exhibit a number of pathological features including age-related neuronal and synaptic loss as well as vascular pathology. They also exhibit increased susceptibility to excitotoxic injury most likely on the basis of exaggerated calcium release from the endoplasmic reticulum. Electrophysiologically long-term potentiation in the hippocampus is increased in young PS1 FAD mutant mice but this effect appears to be lost with aging. In most studies neurogenesis in the adult hippocampus is also impaired by PS1 FAD mutants. Mice in which PS1 has been conditionally knocked out in adult forebrain on a PS2 null background (PS1/2 cDKO) develop a striking neurodegeneration that mimics AD neuropathology in being associated with neuronal and synaptic loss, astrogliosis and hyperphosphorylation of tau, although it is not accompanied by plaque deposits. The relevance of PS transgenic mice as models of AD is discussed.

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Acknowledgments

Work in the authors’ laboratories has been supported by the National Institute on Aging (grants AG02219, AG05138, AG20139, and AG029361), the Alzheimer’s Association (IIRG-07-57318) and a Merit Award from the Department of Veterans Affairs (1I01BX000342).

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Authors and Affiliations

  1. Neurology Service (3E16), James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA

    Gregory A. Elder

  2. Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA

    Gregory A. Elder, Miguel A. Gama Sosa & Rita De Gasperi

  3. Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA

    Gregory A. Elder

  4. Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA

    Miguel A. Gama Sosa & Rita De Gasperi

  5. Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA

    Dara L. Dickstein & Patrick R. Hof

  6. Computational Neurobiology and Imaging Center, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY, 10029, USA

    Dara L. Dickstein & Patrick R. Hof

  7. Department of Geriatrics and Palliative Care, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA

    Patrick R. Hof

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  1. Gregory A. Elder
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  2. Miguel A. Gama Sosa
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Correspondence to Gregory A. Elder.

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Elder, G.A., Gama Sosa, M.A., De Gasperi, R. et al. Presenilin transgenic mice as models of Alzheimer’s disease. Brain Struct Funct 214, 127–143 (2010). https://doi.org/10.1007/s00429-009-0227-3

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