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Am J Pathol. 2016 Feb;186(2):375-84. doi: 10.1016/j.ajpath.2015.10.010. Epub 2015 Dec 11.

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease.

Author information

1
Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts; Department of Neurology, University of Iowa Hospitals & Clinics, Iowa City, Iowa.
2
Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
3
Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; C. S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, Massachusetts.
4
Massachusetts Alzheimer Disease Research Center, Massachusetts General Hospital, Charlestown, Massachusetts; Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: bhyman@mgh.harvard.edu.

Abstract

Amyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312(+) dystrophic neurites, GFAP(+) reactive astrocytes, and IBA1(+) and CD68(+) activated microglia in randomly selected dense-core (Thioflavin-S(+)) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall τ = 0.34, P = 0.001), reactive astrocytes (Kendall τ = 0.30, P = 0.003), and CD68(+) (Kendall τ = 0.48, P < 0.0001), but not IBA1 microglia (Kendall τ = 0.045, P = 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68(+) microglia and symptom duration remained significant (Kendall τ = 0.39, P = 0.0003). The presence of the APOEε4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline.

PMID:
26687817
PMCID:
PMC4729270
DOI:
10.1016/j.ajpath.2015.10.010
[Indexed for MEDLINE]
Free PMC Article

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