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2016 ; 8
(ä): 223
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In vivo Differential Brain Clearance and Catabolism of Monomeric and Oligomeric
Alzheimer s A? protein
#MMPMID27729857
McIntee FL
; Giannoni P
; Blais S
; Sommer G
; Neubert TA
; Rostagno A
; Ghiso J
Front Aging Neurosci
2016[]; 8
(ä): 223
PMID27729857
show ga
Amyloid ? (A?) is the major constituent of the brain deposits found in
parenchymal plaques and cerebral blood vessels of patients with Alzheimer's
disease (AD). Several lines of investigation support the notion that synaptic
pathology, one of the strongest correlates to cognitive impairment, is related to
the progressive accumulation of neurotoxic A? oligomers. Since the process of
oligomerization/fibrillization is concentration-dependent, it is highly reliant
on the homeostatic mechanisms that regulate the steady state levels of A?
influencing the delicate balance between rate of synthesis, dynamics of
aggregation, and clearance kinetics. Emerging new data suggest that reduced A?
clearance, particularly in the aging brain, plays a critical role in the process
of amyloid formation and AD pathogenesis. Using well-defined monomeric and low
molecular mass oligomeric A?1-40 species stereotaxically injected into the brain
of C57BL/6 wild-type mice in combination with biochemical and mass spectrometric
analyses in CSF, our data clearly demonstrate that A? physiologic removal is
extremely fast and involves local proteolytic degradation leading to the
generation of heterogeneous C-terminally cleaved proteolytic products, while
providing clear indication of the detrimental role of oligomerization for brain
A? efflux. Immunofluorescence confocal microscopy studies provide insight into
the cellular pathways involved in the brain removal and cellular uptake of A?.
The findings indicate that clearance from brain interstitial fluid follows local
and systemic paths and that in addition to the blood-brain barrier, local
enzymatic degradation and the bulk flow transport through the choroid plexus into
the CSF play significant roles. Our studies highlight the diverse factors
influencing brain clearance and the participation of various routes of
elimination opening up new research opportunities for the understanding of
altered mechanisms triggering AD pathology and for the potential design of
combined therapeutic strategies.
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