Search results for "BETA-PROTEIN"
showing 10 items of 73 documents
Effects of sulindac sulfide on the membrane architecture and the activity of gamma-secretase.
2007
gamma-Secretase is a membrane-embedded multi-protein complex that catalyzes the final cut of the Alzheimer's disease-related amyloid precursor protein (APP) to amyloid-beta peptides of variable length (37-43 amino acids) via an unusual intramembrane cleavage. Recent findings propose that some commonly used non-steroidal anti-inflammatory drugs (NSAIDs) have the ability to modulate specifically gamma-secretase activity without inhibiting the enzyme as a whole. These drugs may shift the processing of APP from the longer amyloid-beta 42 peptide towards shorter, less fibrillogenic and less toxic amyloid-beta species. We hypothesize that gamma-secretase activity, as an enzyme that is strictly as…
Alcadein cleavages by amyloid beta-precursor protein (APP) alpha- and gamma-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease…
2009
Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc pe…
The Swedish dilemma - the almost exclusive use of APPswe-based mouse models impedes adequate evaluation of alternative β-secretases.
2022
Abstract Alzheimer's disease (AD) is the most common form of dementia, however incurable so far. It is widely accepted that aggregated amyloid β (Aβ) peptides play a crucial role for the pathogenesis of AD, as they cause neurotoxicity and deposit as so-called Aβ plaques in AD patient brains. Aβ peptides derive from the amyloid precursor protein (APP) upon consecutive cleavage at the β- and γ-secretase site. Hence, mutations in the APP gene are often associated with autosomal dominant inherited AD. Almost thirty years ago, two mutations at the β-secretase site were observed in two Swedish families (termed Swedish APP (APPswe) mutations), which led to early-onset AD. Consequently, APPswe was …
Increased AICD generation does not result in increased nuclear translocation or activation of target gene transcription.
2008
A sequence of amyloid precursor protein (APP) cleavages culminates in the sequential release of the APP intracellular domain (AICD) and the amyloid beta peptide (Abeta) and/or p3 fragment. One of the environmental factors favouring the accumulation of AICD appears to be a rise in intracellular pH. Here we further identified the metabolism and subcellular localization of artificially expressed constructs under such conditions. We also co-examined the mechanistic lead up to the AICD accumulation and explored possible significances for its increased expression. We found that most of the AICD generated under pH neutralized conditions is likely cleaved from C83. While the AICD surplus was unable…
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…
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…
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…
Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms.
2014
Postmenopausal women may be more vulnerable to cognitive loss and Alzheimer's disease (AD) than premenopausal women because of their deficiency in estrogens, in addition to their usually older age. Aerobic physical exercise has been proposed as a therapeutic approach for maintaining health and well-being in postmenopausal women, and for improving brain health and plasticity in populations at high risk for AD. To study the neuroprotective mechanisms of physical exercise in a postmenopausal animal model, we submitted previously ovariectomized, six-month old non-transgenic and 3xTg-AD mice to three months of voluntary exercise in a running wheel. At nine months of age, we observed lower grip s…
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…
Restoration of cerebral and systemic microvascular architecture in APP/PS1 transgenic mice following treatment with Liraglutide™.
2015
OBJECTIVE: Cerebral microvascular impairments occurring in AD may reduce Aβ peptide clearance and impact upon circulatory ultrastructure and function. We hypothesized that microvascular pathologies occur in organs responsible for systemic Aβ peptide clearance in a model of AD and that Liraglutide (Victoza(®)) improves vessel architecture. METHODS: Seven-month-old APP/PS1 and age-matched wild-type mice received once-daily intraperitoneal injections of either Liraglutide or saline (n = 4 per group) for eight weeks. Casts of cerebral, splenic, hepatic, and renal microanatomy were analyzed using SEM. RESULTS: Casts from wild-type mice showed regularly spaced microvasculature with smooth lumenal…