Abstract
Soluble oligomeric amyloid β peptide (Aβ) generated from processing of the amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's Disease (AD) and through actions at glutamatergic synapses affects excitability and plasticity. The physiological control of APP processing is not fully understood but stimulation of synaptic NMDA receptors (NMDAR) can suppress Aβ levels through an ERK-dependent increase in α-secretase activity. AMPA-type glutamate receptors (AMPAR) couple to ERK phosphorylation independently of NMDAR activation raising the possibility that stimulation of AMPAR might similarly promote non-amyloidogenic APP processing. We have tested this hypothesis by investigating whether AMPAR directly regulate APP processing in cultured mouse cortical neurons, by analyzing APP C-terminal fragments (CTFs), soluble APP (sAPP), Aβ levels, and cleavage of an APP-GAL4 reporter protein. We report that direct stimulation of AMPAR increases non-amyloidogenic α-secretase-mediated APP processing and inhibits Aβ production. Processing was blocked by the matrix metalloproteinase inhibitor TAPI-1 but was only partially dependent on Ca2+ influx and ERK activity. AMPAR can therefore, be added to the repertoire of receptors that couple to non-amyloidogenic APP processing at glutamatergic synapses and thus pharmacological targeting of AMPAR could potentially influence the development and progression of Aβ pathology in AD.
Highlights
Generation of the amyloid b peptide (Ab) from the amyloid precursor protein (APP) and the subsequent aggregation of Ab as soluble synaptotoxic oligomers, is central to the pathogenesis of Alzheimer’s Disease (AD) [1,2,3,4]
We determined if stimulation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPAR) led to the cleavage of full length of APP, which would be expected if AMPAR couple to APP processing
Cell lysates from cortical neurons treated with vehicle control, AMPA (50 mM) or NMDA (50 mM) for 1 h, were immunoblotted with APP antibody CT20 that is specific for the C-terminal residues 676–695 of APP695, and which will detect all full-length unprocessed cellular APP isoforms
Summary
Generation of the amyloid b peptide (Ab) from the amyloid precursor protein (APP) and the subsequent aggregation of Ab as soluble synaptotoxic oligomers, is central to the pathogenesis of Alzheimer’s Disease (AD) [1,2,3,4]. Synaptic activity enhances Ab release from nerve terminals following endocytosis of APP into endosomes [10,11] and stimulation of presynaptic group II metabotropic glutamate receptors (mGluRs) increases Ab secretion [12]. Postsynaptic group I mGluRs promote non-amyloidogenic asecretase mediated APP processing [13]. Prolonged activation of NMDAR with sub-maximal doses of agonist [14,15] or specific stimulation of extrasynaptic NMDAR [16], promotes amyloidogenic processing of APP and increases Ab production. Direct activation of synaptic NMDAR favours non-amyloidogenic a-secretase-mediated APP processing to reduce Ab production and release [17], first recruiting ADAM-10, towards the cell surface [18] and upregulating ADAM-10 expression in an ERK-dependent manner [19]. Basal activity at NMDAR suppresses Ab levels through a potentially ERK-dependent increase in a-secretase activity suggesting that other receptors found at glutamatergic synapses that act via ERK might suppress Ab production
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