CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology.
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ABSTRACT:
SUBMITTER: Bradshaw EM
PROVIDER: S-EPMC3703870 | biostudies-literature | 2013 Jul
REPOSITORIES: biostudies-literature
Publications
CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology.
Bradshaw Elizabeth M EM Chibnik Lori B LB Keenan Brendan T BT Ottoboni Linda L Raj Towfique T Tang Anna A Rosenkrantz Laura L LL Imboywa Selina S Lee Michelle M Von Korff Alina A Morris Martha C MC Evans Denis A DA Johnson Keith K Sperling Reisa A RA Schneider Julie A JA Bennett David A DA De Jager Philip L PL
Nature neuroscience 20130523 7
In our functional dissection of the CD33 Alzheimer's disease susceptibility locus, we found that the rs3865444(C) risk allele was associated with greater cell surface expression of CD33 in the monocytes (t50 = 10.06, P(joint) = 1.3 × 10(-13)) of young and older individuals. It was also associated with diminished internalization of amyloid-β 42 peptide, accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging, and increased numbers of activated human microglia. ...[more]
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Project description:BACKGROUND:The amyloid precursor protein (APP) is a transmembrane glycoprotein that undergoes alternative proteolytic processing. Its processing through the amyloidogenic pathway originates a large sAPP? ectodomain fragment and the ?-amyloid peptide, while non-amyloidogenic processing generates sAPP? and shorter non-fibrillar fragments. Hence, measuring sAPP? and sAPP? has been proposed as a means to identify imbalances between the amyloidogenic/non-amyloidogenic pathways in the brain of Alzheimer's disease (AD) patients. However, to date, no consistent changes in these proteolytic fragments have been identified in either the brain or cerebrospinal fluid of AD individuals. METHODS:In frontal cortex homogenates from AD patients (n?=?7) and non-demented controls (NDC; n?=?7), the expression of total APP mRNA and that of the APP isoforms generated by alternative splicing, APP695 and APP containing the Kunitz protease inhibitor (KPI), was analyzed by qRT-PCR using TaqMan and SYBR Green probes. The balance between the amyloidogenic/non-amyloidogenic pathways was examined in western blots estimating the sAPP? and sAPP? fragments and their membrane-tethered C-terminal fragments CTF? and CTF?. CHO-PS70 cells, stably over-expressing wild-type human APP, served to evaluate whether A?42 peptide treatment results in altered APP glycosylation. We determined the glycosylation pattern of sAPP? and sAPP? in brain extracts and CHO-PS70 culture media by lectin-binding assays. RESULTS:In the cortex of AD patients, we detected an increase in total APP mRNA relative to the controls, due to an increase in both the APP695 and APP-KPI variants. However, the sAPP? or sAPP? protein levels remained unchanged, as did those of CTF? and CTF?. We studied the glycosylation of the brain sAPP? and sAPP? using lectins and pan-specific antibodies to discriminate between the fragments originated from neuronal APP695 and glial/KPI variants. Lectin binding identified differences in the glycosylation of sAPP? species derived from the APP695 and APP-KPI variants, probably reflecting their distinct cellular origin. Moreover, the lectin-binding pattern differed in the sAPP? and sAPP? originated from all the variants. Finally, when the lectin-binding pattern was compared between AD and NDC groups, significant differences were evident in sAPP? glycosylation. Lectin binding of the soluble sAPP? and sAPP? from CHO-PS70 cells were also altered in cells treated with the A? peptide. CONCLUSION:Our analysis of the lectin binding to sAPP? and sAPP? suggests that glycosylation dictates the proteolytic pathway for APP processing. Differences between the demented and controls indicate that changes in glycosylation may influence the generation of the different APP fragments and, consequently, the pathological progression of AD.
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Project description:In neurodegenerative disorders such as Alzheimer’s disease (AD), brain miRNA profiles are altered; thus miRNA dysfunction could be both a cause and a consequence of disease. Our study dissects the complexity of human AD pathology, in the absence of a post mortem delay, and provides the first miRNA profiling analysis addressing the contribution of amyloid-β (Aβ), a known causative factor of AD, to the de-regulation of neuronal miRNA expression. We used murine primary hippocampal neurons to show that Aβ is a powerful regulator of mature miRNA expression and a prominent miRNA down-regulation is evoked in response to Aβ peptides. Our study provides insight into a previously unexplored mechanism of how Aβ may impact the pathology of AD and identification of key miRNAs affected by Aβ will allow further analysis on target genes and biological pathways contributing to AD pathomechanisms.
2010-05-30 | GSE20447 | GEO