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2014 ; 21
(4
): 582-93
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Microglia convert aggregated amyloid-? into neurotoxic forms through the shedding
of microvesicles
#MMPMID24336048
Joshi P
; Turola E
; Ruiz A
; Bergami A
; Libera DD
; Benussi L
; Giussani P
; Magnani G
; Comi G
; Legname G
; Ghidoni R
; Furlan R
; Matteoli M
; Verderio C
Cell Death Differ
2014[Apr]; 21
(4
): 582-93
PMID24336048
show ga
Alzheimer's disease (AD) is characterized by extracellular amyloid-? (A?)
deposition, which activates microglia, induces neuroinflammation and drives
neurodegeneration. Recent evidence indicates that soluble pre-fibrillar A?
species, rather than insoluble fibrils, are the most toxic forms of A?.
Preventing soluble A? formation represents, therefore, a major goal in AD. We
investigated whether microvesicles (MVs) released extracellularly by reactive
microglia may contribute to AD degeneration. We found that production of myeloid
MVs, likely of microglial origin, is strikingly high in AD patients and in
subjects with mild cognitive impairment and that AD MVs are toxic for cultured
neurons. The mechanism responsible for MV neurotoxicity was defined in vitro
using MVs produced by primary microglia. We demonstrated that neurotoxicity of
MVs results from (i) the capability of MV lipids to promote formation of soluble
A? species from extracellular insoluble aggregates and (ii) from the presence of
neurotoxic A? forms trafficked to MVs after A? internalization into microglia. MV
neurotoxicity was neutralized by the A?-interacting protein PrP and anti-A?
antibodies, which prevented binding to neurons of neurotoxic soluble A? species.
This study identifies microglia-derived MVs as a novel mechanism by which
microglia participate in AD degeneration, and suggest new therapeutic strategies
for the treatment of the disease.
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