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From the Center for Neurologic Diseases,*
Brigham and
Women’s Hospital and Harvard Medical School, Boston, Massachusetts;
Harvard College,
Cambridge, Massachusetts; New
York State Institute for Basic Research and Developmental
Disabilities,
Staten Island, New York; and
the Department of Neurology,§
New York
University, New York, New York
The complement system constitutes a series of enzymatic
steps involved in the inflammatory response and is activated in
Alzheimer’s disease (AD). Using Down’s syndrome (DS) brains as a
temporal model for the progression of AD, we examined
components of the complement cascade and their relationship to other
principal events in AD pathology: Aß42 deposition, neuritic
changes, neurofibrillary tangles (NFTs), and gliosis
(reactive astrocytes, activated microglia). Adjacent sections
of frontal cortex from 24 DS subjects ranging in age from 12 to 73
years were immunohistochemically examined for immunoreactivity (IR) of
classical complement proteins (Clq and C3), markers indicating
activation of complement (C4d and C5b-9), the complement
inhibitor apolipoprotein J (apo J), and markers of AD
neuropathology. Aß42-labeled diffuse plaques were first detected in a
12-year-old DS subject and were not labeled by any of the complement
antibodies. Colocalization of Aß42 with Clq, C3,
C4d, and/or apo J was first detected in compacted plaques in
the brain of a 15-year-old DS patient with features of mature AD
pathology, such as reactive astrocytes, activated
microglia, dystrophic neurites, and a few NFTs. IR for
C4d and C5b-9 (membrane attack complex, MAC) was observed in
small numbers of plaque-associated dystrophic neurites and in focal
regions of pyramidal neurons in this 15-year-old. The only other young
(
30 years) DS brain to show extensive complement IR was that of a
29-year-old DS subject who also displayed the full range of AD
neuropathological features. All middle-aged and old DS brains showed IR
for Clq and C3, primarily in compacted plaques. In these
cases, C4d IR was found in a subset of Aß42 plaques
and, along with C5b-9 IR, was localized to dystrophic
neurites in a subset of neuritic plaques, neurons, and
some NFTs. Our data suggest that in AD and DS, the classical
complement cascade is activated after compaction of Aß42 deposits
and, in some instances, can progress to the local
neuronal expression of the MAC as a response to Aß plaque
maturation.
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