NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production.
Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-beta (Abeta) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of Abeta. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-beta precursor protein (KPI-APP) followed by a shift from alpha-secretase to beta-secretase-mediated APP processing. This shift is a result of the inhibition of the alpha-secretase candidate tumor necrosis factor-alpha converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal Abeta secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase Abeta production and represent a causal risk factor for developing AD.
Lesné
Sylvain
S
Unité Mixte de Recherche, Centre National de la Recherche Scientifique 6185, Centre Cyceron, France.
Ali
Carine
C
Gabriel
Cecília
C
Croci
Nicole
N
MacKenzie
Eric T
ET
Glabe
Charles G
CG
Plotkine
Michel
M
Marchand-Verrecchia
Catherine
C
Vivien
Denis
D
Buisson
Alain
A
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism* / Q000502:physiology
D016229:Amyloid beta-Peptides; D018690:Excitatory Amino Acid Agonists; D011480:Protease Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse