O4‐06–01: APP and PRPC physiological metabolisms are both controlled by muscarinic receptors via ADAM17 phosphorylation
Year: 2008
Type: article
Abstract: Alzheimer's disease (AD) and prion diseases are fatal neurodegenerative syndromes against which no efficient treatments are available nowadays. Although these pathologies are distinct by several aspects (incidence, infectious character of prions), they display common features such as the deposition of insoluble proteinaceous aggregates in the brain. Interestingly, the beta-amyloid precursor protein (betaAPP) and the cellular prion protein (PrPc), the two culprit proteins in AD and prion-associated pathologies respectively, are similarly processed in the middle of their toxic core. Indeed, the so-called alpha-secretase cleavage precludes the integrity of the amyloid-beta peptide (Abeta) and the 106–126 sequence of PrPc. The recent identification of members of the disintegrin family of proteases, ADAM10/ADAM9 and ADAM17, as constitutive and PKC-regulated alpha-secretase activities cleaving both betaAPP and PrPc further reinforced the link between Alzheimer's and prion diseases. The goal of the present study was to identify the receptors, ligands and enzymes operating upstream and downstream of PKC that ultimately leads to the up-regulation of both betaAPP and PrPc alpha-secretase processing. We used human HEK293 cells overexpressing each of the four muscarinic receptors as well as primary neurons which express endogenous levels of these proteins. By means of immunoprecipitation and western blotting with specific antibodies, we monitored the effects of several muscarinic agonists on both betaAPP and PrPc alpha-secretase processing. Furthermore, we examined the effect of muscarinic receptor activation on the phosphorylation state of ADAM17 along its intra-cytoplasmic sequence. We demonstrated that the M1/M3 muscarinic receptors which are coupled to PLC/PKC, but not the M2/M4 (linked to adenylate cyclase/PKA) were key components of the PKC-mediated alpha-secretase processing of betaAPP and PrPc both in primary cultured neurons and in transfected HEK293 cells. Furthermore, activation of these receptors led to the phosphorylation of ADAM17 on its threonine735, the subsequent increase of its enzymatic activity and, ultimately, increased N1 and sAPPalpha secretion in the extracellular space. Altogether, these data further reinforced the fact that Alzheimer and prion diseases share several common denominators and suggest that any medication aiming at increasing the alpha-secretase cleavage of betaAPP and PrPc could ameliorate two apparently unrelated groups of neurodegenerative syndromes.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1997865663