Abstract
Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Aβ oligomers without Aβ plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Aβ oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Aβ oligomers in the onset of AD and suggests that Aβ plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Aβ oligomers in AD pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Humans
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Longevity*
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Memory
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microglia / metabolism
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Microglia / pathology
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Models, Animal
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Models, Biological*
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Neurofibrillary Tangles / metabolism
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Neurofibrillary Tangles / pathology
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Neurofibrillary Tangles / ultrastructure
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Neuronal Plasticity
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Neurons / metabolism
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Peptide Fragments / metabolism
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Phosphorylation
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Plaque, Amyloid / metabolism
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Plaque, Amyloid / pathology
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Plaque, Amyloid / physiopathology
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Plaque, Amyloid / ultrastructure
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Protein Multimerization*
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Synapses / metabolism
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Synapses / pathology
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Synapses / ultrastructure
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tau Proteins / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Peptide Fragments
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amyloid beta-protein (1-42)
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tau Proteins
Grants and funding
This work was supported by CHINA-CANADA Joint Initiative on Alzheimer's Disease and Related Disorders (812111340), the National Science and Technology Major Projects for “Major New Drug Innovation and Development” of the Twelfth 5-year Plan Period (2011ZX09307-001-02), and the major project of the Science and Technology Plan of the Beijing Municipal Science & Technology Commission (SCW 2011-10). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.