ADAM10 expression and promoter haplotype in Alzheimer's disease

Abstract

Alzheimer’s disease is confirmed at autopsy according to the accumulation of brain neuritic plaques and neurofibrillary tangles in the brain. Neuritic plaques contain Aβ and lower levels of Aβ correspond to an increase in ADAM10 α-secretase activity. ADAM10 α-secretase activity produces a soluble APP alpha (sAPPα) product and negates the pathological production of Aβ. In this investigation it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as CSF sAPPα levels. Results from this investigation suggest that the ADAM10 rs514049–rs653765 C-A promoter haplotype is associated with; 1) higher CSF sAPPα levels in cognitively normal controls compared to AD, 2) higher post mortem brain hippocampus, but not cerebellum, ADAM10 protein levels in low plaque score subjects compared to high plaque score subjects and 3) higher promoter activity for promoter only reporter constructs compared to promoter – 3′UTR constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines. Taken together, these findings suggest that ADAM10 expression is modulated according to a promoter haplotype that is influenced in a brain region and cell type specific manner.

Pathophysiological Function of ADAMTS Enzymes on Molecular Mechanism of Alzheimer’s Disease

“…In the cases with AD, extensity scores of immunohistochemical staining for β-APP (51-75%vs51-75%), ADAM9 (50-75%vs26-50%), ADAM10 (76-100% vs 0-25%), and ADAM17 (76-100%vs 0%) were detected as indicated in parentheses [unpublished observations). Bekris et al [65] reported elevated CSF sAPPα levels in cognitively normal subjects compared with patients with AD and higher hippocampus ADAM10 protein levels in subjects with a low neuritic plaque score compared with those with a high neuritic plaque score. ADAM10 mRNA expression is higher in AD patients compared with control subjects in cerebellum, but not in hippocampus [65].…”

“…Cleavage of APP by α-secretase releases a large, soluble N-terminal ectodomain, soluble α-secretase-released Nterminal APP domain (sAPPα), into the extracellular space [62]. Several studies have reported that α secretases exerted proteolytic effects on APP preventing production, and accumulation of Aβ proteins in AD [22,[62][63][64][65]. The important roles of ADAM9, -10, and -17 in these processes such as APP amyloid cascade, functioning of pathogenetic processes, and subtypes of amyloid proteins are already known [22,63,64].…”

“…These proteases prevent production, accumulation of Aβ proteins from APP, and antagonize the activities of amyloids via various mechanisms with potential trophic effects on nerve tissue [22,64,66]. Additionally, several groups have been reported that the levels of ADAM10, which is especially effective on proteolytic processes involving APP, decreased in AD [65,67,68]. An increase in ADAM10 levels in a mouse model corresponded to a decrease in Aβ plaque levels [69].…”

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“…Alternatively, in the trophic, anti-amyloidogenic anti-AD pathway, APP is cleaved by an α-secretase (putatively ADAM10) to generate the two fragments sAPPα and αCTF. These latter fragments [30] support synaptic maintenance and can inhibit the β pathway as cleavage at the α site precludes β cleavage and because sAPPα itself is a BACE inhibitor [31,32].…”

“…Alternatively, in the trophic, anti-amyloidogenic anti-AD pathway, APP is cleaved by an α-secretase (putatively ADAM10) to generate the two fragments sAPPα and αCTF. These latter fragments [30] support synaptic maintenance and can inhibit the β pathway as cleavage at the α site precludes β cleavage and because sAPPα itself is a BACE inhibitor [31,32].The interaction of APP cleavage products with each other and non-APP-derived proteins is complex and the mechanisms by which these APP fragments exert their many effects is not fully elucidated [34]. It is known, however, that αCTF can inhibit γ-secretase activity [33] as it contains an intact γ-cleavage site.…”