Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors.

Abstract

aggregates that may be toxic to neurons (9-11). Neurotransmitters can regulate APP processing to favor the secretion of APPS (12). In human embryonic kidney (HEK) 293 cells stably expressing the human muscarinic receptor subtypes ml or m3, stimulation with the muscarinic agonist carbachol increased APP, secretion. The muscarinic receptors mediating this effect (ml and m3 but not m2 or m4) are coupled to intracellular signaling pathways via second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (InsP3), which are generated by phosphatidylinositol 4,5-bisphosphate (PtdInsP2) hydrolysis. In other established cell lines, accelerated APP metabolism produced by direct stimulation of protein kinase C (PKC) or inhibition of phosphatase activity also increased APP, secretion (13-16). In HEK 293 cells overexpressing ml receptors, there was a reciprocal relationship between APP, and AP3 secretion after receptor activation with carbachol (17); thus, receptor activation can enhance APP, secretion and also suppress AP3 formation.Abundant levels of both APP message and protein are present in neurons. The detection of APP, in plasma and cerebrospinal fluid (18,19) suggests that proteolysis of APP into soluble derivatives occurs in the central nervous system. Because receptor activation can regulate APP processing, impaired neurotransmission could conceivably exacerbate amyloid formation in AD, particularly in cortex and hippocampus. In addition to the loss of cholinergic basal forebrain neurons (20), glutamatergic corticocortical connections and major projections of the hippocampus are especially vulnerable to damage in AD (21). These pathways atrophy during the early stages of the disease, and in postmortem brain glutamate concentrations are decreased by as much as 80% (22). Because glutamate activates PKC in nervous tissue (23, 24), we tested the hypothesis that glutamate might divert APP processing from amyloidogenic pathways and, instead, favor increased APPs secretion.Metabotropic glutamate receptors (mGluR) are coupled to the formation of multiple second messengers via activation of phospholipase enzymes (23-25). Nonselective glutamate agonists [e.g., L-glutamate, quisqualate (QA)] can interact with both mGluR and ionotropic glutamate receptors (iGluR), but the selective mGluR agonist, trans-(1S,3R)-l-amino-1,3-cyclopentane dicarboxylic acid (ACPD) initiates signal transduction without affecting the iGluR. mGluR exist as seven subtypes and are categorized into three major groups on the

P2Y2 Nucleotide Receptors Enhance α-Secretase-dependent Amyloid Precursor Protein Processing

“…Utilizing the human 1321N1 astrocytoma cell line that lacks endogenous P2 receptor expression, we demonstrate that stable transfection with P2Y 2 R cDNA promoted UTP-induced release of sAPP␣ in a time-and dose-dependent manner, similar to sAPP␣ release mediated by muscarinic, glutamate, bradykinin, and serotonergic receptors (37)(38)(39)(40)(41)(42).…”

A femtomolar-acting neuroprotective peptide.

“…Activation of the NMDA-responsive receptor (ionotropic glutamate receptor) may induce an increase in the amyloid precursor protein level (61). This increase, coupled with deficits in glutaminergic transmission (metabotropic glutamate receptors), which have been observed in Alzheimer's brains, may hinder the breakdown of amyloid precursor protein, which normally forms soluble, nonamyloidergic derivatives in vivo (62). It is possible that ADNF inhibits neurotoxicity by influencing Ca ϩϩ mobilization.…”

β-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons

“…Anchoring proteins that are involved in PKC signal transduction seem to contribute to this PKC activation deficit (Battaini et al 1997). Because the stimulation of PKC by mGluRs increases the nonamyloidogenic, secretory pathway of APP processing (Lee et al 1995), the disrupted mGluR activation of PKC in AD may inhibit the nonamyloidogenic APP processing pathway and lead to increased ␤-amyloid production. Enhanced A␤ generation, in turn, exacerbates mGluR abnormalities, causing the dysfunction of glutamatergic synapses.…”