Abstract
Mutations in the amyloid precursor protein (APP) gene result in elevated production and deposition of the 42 amino acid beta-amyloid (Abeta1-42) peptide and early-onset Alzheimer's disease (AD). To accurately examine the effect of the APP FAD mutations in vivo, we introduced yeast artificial chromosomes (YACs) containing the entire genomic copy of human APP harboring FAD mutations into transgenic mice. Our current results demonstrate that mutant APP YAC transgenic mice exhibit many features characteristic of human AD, including regional deposition of Abeta with preferential deposition of Abeta1-42, extensive neuritic abnormalities as evidenced by staining with APP, ubiquitin, neurofilament, and hyperphosphorylated tau antibodies, increased markers of inflammation, and the overlapping deposition of Abeta with apolipoproteins E and J. Our results also suggest that APP YAC transgenic mice possess unique pathological attributes when compared to other transgenic mouse models of AD that may reflect the experimental design of each model.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aging / genetics
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Aging / metabolism
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Aging / pathology
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Alzheimer Disease / genetics*
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / genetics*
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Apolipoproteins E / genetics
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Apolipoproteins E / metabolism
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Brain / metabolism*
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Brain / pathology*
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Brain / physiopathology
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Chromosomes, Artificial, Yeast / genetics*
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Clusterin
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Female
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Gene Targeting / methods*
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Humans
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Immunohistochemistry
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism
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Mutation / genetics*
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Neurites / metabolism
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Neurites / pathology
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Neuroglia / metabolism
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Neuroglia / pathology
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Neurons / metabolism
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Neurons / pathology
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Plaque, Amyloid / genetics
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Plaque, Amyloid / metabolism
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Plaque, Amyloid / pathology
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Presenilin-1
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Sex Characteristics
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Apolipoproteins E
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CLU protein, human
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Clu protein, mouse
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Clusterin
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Glycoproteins
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Membrane Proteins
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Molecular Chaperones
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PSEN1 protein, human
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Peptide Fragments
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Presenilin-1
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)