Journal
JOURNAL OF NEUROCHEMISTRY
Volume 128, Issue 3, Pages 350-362Publisher
WILEY-BLACKWELL
DOI: 10.1111/jnc.12471
Keywords
APP(-/-) mice; A beta 40; ERK/mTOR pathway cerebellar granule neurons; GABA(A)6 subunit; p75(NTR)
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Funding
- National Natural Science Foundation of China [NSFC 31070745]
- Shanghai Leading Academic Discipline Project [B111]
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In addition to their neurotoxic role in Alzheimer's disease (AD), -amyloid peptides (As) are also known to play physiological roles. Here, we show that recombinant A40 significantly increased the outward current of the GABA(A) receptor containing (GABA(A)6) in rat cerebellar granule neurons (CGNs). The A40-mediated increase in GABA(A)6 current was mediated by an increase in GABA(A)6 protein expression at the translational rather than the transcriptional level. The exposure of CGNs to A40 markedly induced the phosphorylation of ERK (pERK) and mammalian target of rapamycin (pmTOR). The increase in GABA(A)6 current and expression was attenuated by specific inhibitors of ERK or mTOR, suggesting that the ERK and mTOR signaling pathways are required for the effect of A40 on GABA(A)6 current and expression in CGNs. A pharmacological blockade of the p75 neurotrophin receptor (p75(NTR)), but not the insulin or 7-nAChR receptors, abrogated the effect of A40 on GABA(A)6 protein expression and current. Furthermore, the expression of GABA(A)6 was lower in CGNs from APP(-/-) mice than in CGNs from wild-type mice. Moreover, the internal granule layer (IGL) in APP(-/-) mice was thinner than the IGL in wild-type mice. The injection of A40 into the cerebellum reversed this effect, and the application of p75(NTR) blocking antibody abolished the effects of A40 on cerebellum morphology in APP(-/-) mice. Our results suggest that low concentrations of A40 play a role in regulating CGN maturation through p75(NTR).
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