Abstract
Although amyloid deposition was noted by Alzheimer in 1907 (1), it has been only 17 years since the toxicity of Aβ2 was first described (2). The prevailing view through most of the twentieth century was that Aβ is a marker of disease progression in AD but does not play a role in the neurodegenerative process. This view changed in the 1990s with the articulation of the amyloid hypothesis, which posits that abnormal accumulation of Aβ in the brain is a direct cause of neurodegeneration and cognitive decline in AD. The hypothesis is supported by the identification of mutations in APP (3) and presenilins 1 and 2 (4–7) that increase Aβ generation or, more importantly, the generation of a minor 42-amino acid form (Aβ42) with an increased propensity for aggregation (8). This review sets forth the major lines of evidence for Aβ toxicity and focuses on the interface between Aβ toxicity and molecular mechanisms of synaptic plasticity.
Highlights
Transgenic mouse models expressing APP and presenilin variants associated with FAD have provided important insights into structural, neurophysiological, and behavioral effects of
When the APP transgenic was placed on an apoE-deficient background, A deposition still occurred, but fibrillar deposits were absent, and neuritic dystrophy was markedly reduced
Plaque formation was followed by progressive neuritic abnormalities that appeared in direct contiguity to the plaque, establishing a causal relationship between amyloid deposition and neuritic dystrophy [19]
Summary
Transgenic mouse models expressing APP and presenilin variants associated with FAD have provided important insights into structural, neurophysiological, and behavioral effects of. The neuritic dystrophy observed in APP transgenic mice appears to be directly related to the fibrillar component of A deposits. A limitation of APP transgenic mouse models is the paucity of neuronal cell death and tau-related pathology characteristic of human AD [21, 22].
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