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The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in alzheimer's disease-like transgenic mice.

Abstract：

:A previous study in our laboratory, involving early stage, amyloid pathology in 8-month-old transgenic mice, demonstrated a selective loss of cholinergic terminals in the cerebral and hippocampal cortices of doubly transgenic (APP(K670N,M671L)+PSl(M146L)) mice, an up-regulation in the single mutant APP(K670N,M671L) mice and no detectable change in the PSl(M146L) transgenics [J Neurosci 19 (1999) 2706]. The present study investigates the impact of amyloid plaques on synaptophysin and vesicular acetylcholine transporter (VAChT) immunoreactive bouton numbers in the frontal cortex of the three transgenic mouse models previously described. When compared as a whole, the frontal cortices of transgenic and control mice show no observable differences in the densities of synaptophysin-immunoreactive boutons. An individual comparison of layer V of the frontal cortex, however, shows a significant increase in density in transgenic models. Analysis of the cholinergic system alone shows significant alterations in the VAChT-immunoreactive bouton densities as evidenced by an increased density in the single (APP(K670N,M671L)) transgenics and a decreased density in the doubly transgenics (APP(K670N,M671L)+PSl(M146L)). In investigating the impact of plaque proximity on bouton density at early stages of the amyloid pathology in our doubly (APP(K670N,M671L)+PSl(M146L)) transgenic mouse line, we observed that plaque proximity reduced cholinergic pre-synaptic bouton density by 40%, and yet increased synaptophysin-immunoreactive pre-synaptic bouton density by 9.5%. Distance from plaques (up to 60 microm) seemed to have no effect on bouton density; however a significant inverse relationship was visible between plaque size and cholinergic pre-synaptic bouton density. Finally, the number of cholinergic dystrophic neurites surrounding the truly amyloid, Thioflavin-S(+) plaque core, was disproportionately large with respect to the incidence of cholinergic boutons within the total pre-synaptic bouton population. Confocal and electron microscopic observations confirmed the preferential infiltration of dystrophic cholinergic boutons into fibrillar amyloid aggregates. We therefore hypothesize that extracellular Abeta aggregation preferentially affects cholinergic terminations prior to progression onto other neurotransmitter systems. This is supported by the observable presence of non-cholinergic sprouting, which may be representative of impending neuritic degeneration.

journal_name

Neuroscience

journal_title

Neuroscience

authors

Hu L,Wong TP,Côté SL,Bell KF,Cuello AC

doi

10.1016/s0306-4522(03)00394-4

keywords:

subject

Has Abstract

pub_date

2003-01-01 00:00:00

pages

421-32

issue

eissn

0306-4522

issn

1873-7544

pii

S0306452203003944

journal_volume

121

pub_type

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The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in alzheimer's disease-like transgenic mice.