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      Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation

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          Abstract

          Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of β-amyloid 42 (Aβ 42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Aβ 42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Aβ 42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Aβ 42 production. 5XFAD mice generate Aβ 42 almost exclusively and rapidly accumulate massive cerebral Aβ 42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal Aβ 42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal Aβ. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ 42-induced neurodegeneration and amyloid plaque formation.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          4 October 2006
          : 26
          : 40
          : 10129-10140
          Affiliations
          [1]Departments of 1Cell and Molecular Biology and
          [2] 2Physiology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611
          Author notes
          Correspondence should be addressed to Dr. Robert Vassar, Department of Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611. r-vassar@ 123456northwestern.edu
          Article
          PMC6674618 PMC6674618 6674618 3151555
          10.1523/JNEUROSCI.1202-06.2006
          6674618
          17021169
          490871eb-8a1a-4073-a5c8-5f43c610bc51
          Copyright © 2006 Society for Neuroscience 0270-6474/06/2610129-13$15.00/0
          History
          : 20 March 2006
          : 24 July 2006
          : 24 August 2006
          Categories
          Articles
          Neurobiology of Disease
          Custom metadata

          neuron loss,intraneuronal Aβ,amyloid plaques,Aβ42 ,transgenic mice,Alzheimer's disease

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