Expression of human amyloid precursor protein in rat cortical neurons inhibits calcium oscillations.
Synchronous calcium oscillations are observed in primary cultures of rat cortical neurons when mature networks are formed. This spontaneous neuronal activity needs an accurate control of calcium homeostasis. Alteration of intraneuronal calcium concentration is described in many neurodegenerative disorders, including Alzheimer disease (AD). Although processing of amyloid precursor protein (APP) that generates Abeta peptide has critical implications for AD pathogenesis, the neuronal function of APP remains unclear. Here, we report that expression of human APP (hAPP) in rat cortical neurons increases L-type calcium currents, which stimulate SK channels, calcium-dependent K(+) channels responsible for medium afterhyperpolarization (mAHP). In a neuronal network, increased mAHP in some neurons expressing hAPP leads to inhibition of calcium oscillations in all the cells of the network. This inhibition is independent of production and secretion of Abeta and other APP metabolites. In a neuronal network, reduction of endogenous APP expression using shRNA increases the frequency and reduces the amplitude of calcium oscillations. Altogether, these data support a key role for APP in the control of neuronal excitability.
Experimental Pharmacology Unit, Institute of Neuroscience, Université catholique de Louvain, B-1200 Brussels, Belgium.
Susana Ferrao
SF
Santos
Nathalie
N
Pierrot
Nicole
N
Morel
Philippe
P
Gailly
Christian
C
Sindic
Jean-Noël
JN
Octave
D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D016564:Amyloid beta-Protein Precursor; D020746:Calcium Channels, L-Type; D034741:RNA, Small Interfering; D002118:Calcium