Search results for "Alpha secretase"

A Closer Look at α-Secretase

2008

Accumulation of amyloid beta-peptides (Abeta) in the brain is believed to contribute to the development of Alzheimer disease (AD). Abeta, a 40-42 amino acid-comprising proteolytical fragment of the amyloid precursor protein (APP), is released from APP by sequential cleavages via beta- and gamma-secretases. However, the predominant route of APP processing consists of successive cleavages by alpha- and gamma-secretases. Alpha-secretase attacks APP inside the Abeta sequence, and therefore prevents formation of neurotoxic Abeta. After cleavage by alpha-secretase, the soluble N-terminal domain of APP, which possesses neurotrophic and neuroprotective properties, is released. In AD patients, a dec…

Influence of ADAM10 on prion protein processing and scrapie infectiosity in vivo.

2009

Abstract Both the cellular prion protein (PrPc) and the amyloid precursor protein (APP) are physiologically subjected to complex proteolytic processing events. While for APP the proteinases involved – alpha-, beta- and gamma-secretase – have been identified in vitro and in vivo, the cleavage of PrPc by now has been linked only to the shedding activity of the metalloproteinase ADAM10 and/or ADAM17 in cell culture. Here we show that neuronal overexpression of the alpha-secretase ADAM10 in mice reduces all PrPc species detected in the brain instead of leading to enhanced amounts of specific cleavage products of PrPc. Additionally, the incubation time of mice after scrapie infection is signific…

[S2‐01‐01]: Alpha‐secretase as a therapeutic target

2005

Regulation of the alpha-secretase ADAM10 by its prodomain and proprotein convertases.

2001

SPECIFIC AIMSTo identify the proprotein convertases responsible for maturation of the α-secretase ADAM10, we investigated the influence of PC7 and furin on ADAM10 processing and the resulting effect on amyloid precursor protein cleavage. We also examined the functional role of the ADAM10 prodomain by coexpression of a prodomain-deleted ADAM10 mutant together with its prodomain in trans.PRINCIPAL FINDINGS1. ADAM10 is proteolytically processed by PC7 and furinThe disintegrin metalloproteinase ADAM10 possesses α-secretase activity as well as a potential proprotein convertase recognition sequence (RKKR) after its prodomain. By amino-terminal sequencing of ADAM10 purified from bovine kidney plas…

Alpha-secretase activation--an approach to Alzheimer's disease therapy.

2006

The nonamyloidogenic pathway of processing the amyloid precursor protein (APP) involves the cleavage within the amyloid-beta peptide sequence, and thus precludes amyloid-beta formation. The identification of a member of the disintegrin and metalloproteinase family, ADAM10, as an alpha-secretase that prevents plaque formation and hippocampal deficits in vivo gave us the possibility to examine the alpha-secretase as a potential target for the therapy of Alzheimer's disease. Within the priority program Cellular Mechanisms of Alzheimer's Disease, we investigated several approaches to stimulate the alpha-secretase pathway. Two protein convertases were found to be responsible for the removal of t…

The Role of the anti-amyloidogenic secretase ADAM10 in shedding the APP-like proteins.

2011

ADAM10 (A disintegrin and metalloproteinase 10) has been demonstrated as an enzyme with protective properties in Alzheimer's disease: in mouse models it not only lowered generation of toxic A-beta peptides and formation of senile plaques but also alleviated learning deficits and enhanced synaptic density. This is due to cleavage of the amyloid precursor protein (APP) within its A-beta stretch and to the release of the extracellular domain of APP with neuroprotective function. Aside from cleaving APP, ADAM10 has been linked to over 40 putative substrates at least in cell culture. These substrates are connected with important cellular functions such as cell migration, stress response and tran…

The Non-Amyloidogenic Pathway: Structure and Function of α-Secretases

2006

The amyloid cascade hypothesis is the most accepted explanation for the pathogenesis of Alzheimer’s disease (AD). APP is the precursor of the amyloid β peptide (Aβ), the principal proteinaceous component of amyloid plaques in brains of Alzheimer’s disease patients. Proteolytic cleavage of APP by the α-secretase within the Aβ sequence precludes formation of amyloidogenic peptides and leads to a release of soluble APPsα which has neuroprotective properties. In several studies, a decreased amount of APPsα in the cerebrospinal fluid of AD patients has been observed. Three members of the ADAM family (a disintegrin and metalloproteinase) ADAM-10, ADAM-17 (TACE) and ADAM-9 have been proposed as α-…

P3‐271: Presenilin‐1 (PS1) and amyloid precursor protein (APP) mutations present in mouse models of Alzheimer's disease in their response to γ‐secret…

2009

Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10

2001

Biochemical, epidemiological, and genetic findings demonstrate a link between cholesterol levels, processing of the amyloid precursor protein (APP), and Alzheimer's disease. In the present report, we identify the α-secretase ADAM 10 ( a d isintegrin a nd m etalloprotease) as a major target of the cholesterol effects on APP metabolism. Treatment of various peripheral and neural cell lines with either the cholesterol-extracting agent methyl-β-cyclodextrin or the hydroxymethyl glutaryl-CoA reductase inhibitor lovastatin resulted in a drastic increase of secreted α-secretase cleaved soluble APP. This strong stimulatory effect was in the range obtained with phorbol esters and was further increa…

α-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation

2009

The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer's disease due to increased cleavage of APP by BACE1. While beta-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show that liberation of Abeta from APPswe is still dependent on functional internalization from the cell surface. Inspite the unchanged overall beta-secretase cleaved soluble APP released from APP(swe) secretion, mutations of the APPswe internalization motif strongly reduced C99 levels and substantially decreased Abeta secretion. We point out t…