γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aß.
Eur J Neurosci
; 37(10): 1714-25, 2013 May.
Article
in En
| MEDLINE
| ID: mdl-23432732
ABSTRACT
Deposition of ß -amyloid (Aß) peptides, cleavage products of ß-amyloid precursor protein (APP) by ß-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aß approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aß peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aß efficacy. The present study compared active γ-secretase binding sites with Aß deposition in aged and AD human cerebrum, and explored the possibility of Aß production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and ß-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aß40 and Aß42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aß, probably at reduced levels in AD.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptide Fragments
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Choroid Plexus
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Amyloid beta-Peptides
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Amyloid Precursor Protein Secretases
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Cerebrum
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Alzheimer Disease
Limits:
Aged
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Aged80
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Animals
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
Eur J Neurosci
Journal subject:
NEUROLOGIA
Year:
2013
Type:
Article
Affiliation country:
China