Summary
The accumulation of amyloid-β (Aβ) as amyloid fibrils and
toxic oligomers is an important step in the development of Alzheimer's disease
(AD). However, there are numerous potentially toxic oligomers and little is
known about their neurological effects when generated in the living brain. Here,
we show that Aβ oligomers can be assigned to one of at least two classes
(Type 1 and Type 2) based on their temporal, spatial and structural
relationships to amyloid fibrils. The Type 2 oligomers are related to amyloid
fibrils and represent the majority of oligomers generated in
vivo, but remain confined to the vicinity of amyloid plaques and do
not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to
amyloid fibrils and may have greater potential to cause global neural
dysfunction in AD because they are dispersed. These results refine our
understanding of the pathogenicity of Aβ oligomers in
vivo.
There exist several dozen lines of transgenic mice that express human
amyloid-β precursor protein (AβPP) with Alzheimer’s
disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the
types and amounts of Aβ that they generate and in their spatiotemporal
patterns of expression of Aβ assemblies, providing a toolkit to study
Aβ amyloidosis and the influence of Aβ aggregation on brain
function. More complete quantitative descriptions of the types of Aβ
assemblies present in transgenic mice and in humans during disease progression
should add to our understanding of how Aβ toxicity in mice relates to
the pathogenesis of AD. Here, we provide a direct quantitative comparison of
amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic
mice. We measured the fraction of cortex and hippocampus occupied by dense-core
plaques, visualized by staining with Thioflavin S, in mice from young adulthood
through advanced age. We found that the plaque burdens among the transgenic
lines varied by an order of magnitude: at 15 months of age, the oldest age
studied, the median cortical plaque burden in 5XFAD mice was already
~4.5 times that of 21-month Tg2576 mice and ~15 times that of
21–24-month rTg9191 mice. Plaque-size distributions changed across the
lifespan in a line- and region-dependent manner. We also compared the dense-core
plaque burdens in the mice to those measured in a set of
pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in
Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded
those measured in the human cohort.
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