Search results for "Amyloid Precursor Protein"

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

A practical entry to β-aryl-β-alkyl amino alcohols: application to the synthesis of a potent BACE1 inhibitor

2012

The 1,2-addition of alkyl Grignard reagents to readily available N-tert-butanesulfinyl ketimines, bearing an α-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present method was demonstrated by the synthesis, in enantiomerically pure form, of one recently disclosed β-secretase (BACE1) inhibitor.

Independent Generation of Aβ42 and Aβ38 Peptide Species by γ-Secretase

2008

Proteolytic processing of the amyloid precursor protein by beta- and gamma-secretase generates the amyloid-beta (Abeta) peptides, which are principal drug targets in Alzheimer disease therapeutics. gamma-Secretase has imprecise cleavage specificity and generates the most abundant Abeta40 and Abeta42 species together with longer and shorter peptides such as Abeta38. Several mechanisms could explain the production of multiple Abeta peptides by gamma-secretase, including sequential processing of longer into shorter Abeta peptides. A novel class of gamma-secretase modulators (GSMs) that includes some non-steroidal anti-inflammatory drugs has been shown to selectively lower Abeta42 levels withou…

Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases.

2008

The receptor for advanced glycation end products (RAGE) is a 55-kDa type I membrane glycoprotein of the immunoglobulin superfamily. Ligand-induced up-regulation of RAGE is involved in various pathophysiological processes, including late diabetic complications and Alzheimer disease. Application of recombinant soluble RAGE has been shown to block RAGE-mediated pathophysiological conditions. After expression of full-length RAGE in HEK cells we identified a 48-kDa soluble RAGE form (sRAGE) in the culture medium. This variant of RAGE is smaller than a 51-kDa soluble version derived from alternative splicing. The release of sRAGE can be induced by the phorbol ester PMA and the calcium ionophore c…

Retinoids as a Perspective in Treatment of Alzheimer’s Disease

2010

<i>Background:</i> In the past, we demonstrated that the disintegrin metalloproteinase ADAM10 has α-secretase activity in vitro and in cultured cells. We also found out that moderate overexpression of this proteinase inhibits Aβ peptide production and prevents the formation of amyloid plaques in an Alzheimer’s disease (AD) mouse model. Moreover, it corrects early hippocampal defects like LTP impairment and increases cortical synaptogenesis. <i>Objective:</i> Upregulation of ADAM10 might be an alternative approach concerning AD therapy. Our current research therefore focuses on substances and/or pathways which regulate ADAM10 gene expression. <i>Methods:</i&g…

Melatonin stimulates the nonamyloidogenic processing ofβAPP through the positive transcriptional regulation of ADAM10 and ADAM17

2014

Melatonin controls many physiological functions including regulation of the circadian rhythm and clearance of free radicals and neuroprotection. Importantly, melatonin levels strongly decrease as we age and patients with Alzheimer's disease (AD) display lower melatonin than age-matched controls. Several studies have reported that melatonin can reduce aggregation and toxicity of amyloid-β peptides that are produced from the β-amyloid precursor protein (βAPP). However, whether melatonin can directly regulate the βAPP-cleaving proteases ('secretases') has not been investigated so far. In this study, we establish that melatonin stimulates the α-secretase cleavage of βAPP in cultured neuronal an…

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…

Nonsteroidal Anti-Inflammatory Drugs and Ectodomain Shedding of the Amyloid Precursor Protein

2008

<i>Background:</i> Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer’s disease (AD). Several mechanisms have been proposed to explain these findings including increased shedding of the soluble ectodomain of the amyloid precursor protein (sAPP), which functions as a neurotrophic and neuroprotective factor in vitroand in vivo. <i>Objective:</i> To clarify whether NSAIDs consistently stimulate sAPP secretion. <i>Methods:</i> 293-EBNA cells with stable overexpression of an APP-alkaline phosphatase fusion protein (APP-AP), SH-SY5Y and PC12 cells or prim…

Regulated Proteolysis of RAGE and AβPP as Possible Link Between Type 2 Diabetes Mellitus and Alzheimer's Disease

2009

Epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of developing Alzheimer's disease (AD). In T2DM, the elevated blood glucose level promotes formation of advanced glycation end products (AGEs). The receptor for AGEs (RAGE) is a type I membrane-protein and is also able to import amyloid-beta (Abeta) from the blood across the blood-brain-barrier into the brain. Oligomeric Abeta peptides disturb synaptic function in the brain and are believed to contribute to the development of AD. Abeta peptides are released from the amyloid-beta protein precursor (AbetaPP) after sequential proteolysis by beta- and gamma-secretases but alpha-secretase-mediated cleavage…