Abeta40 modulates GABA(A) receptor alpha6 subunit expression and rat cerebellar granule neuron maturation through the ERK/mTOR pathway.

Authors: Zhan, XQ  Yao, JJ  Liu, DD  Ma, Q  Mei, YA 
Citation: Zhan XQ, etal., J Neurochem. 2014 Feb;128(3):350-62. doi: 10.1111/jnc.12471. Epub 2013 Oct 24.
Pubmed: (View Article at PubMed) PMID:24118019
DOI: Full-text: DOI:10.1111/jnc.12471

In addition to their neurotoxic role in Alzheimer's disease (AD), beta-amyloid peptides (Abetas) are also known to play physiological roles. Here, we show that recombinant Abeta40 significantly increased the outward current of the GABA(A) receptor containing (GABA(A)alpha6) in rat cerebellar granule neurons (CGNs). The Abeta40-mediated increase in GABA(A)alpha6 current was mediated by an increase in GABA(A)alpha6 protein expression at the translational rather than the transcriptional level. The exposure of CGNs to Abeta40 markedly induced the phosphorylation of ERK (pERK) and mammalian target of rapamycin (pmTOR). The increase in GABA(A)alpha6 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 Abeta40 on GABA(A)alpha6 current and expression in CGNs. A pharmacological blockade of the p75 neurotrophin receptor (p75(NTR)), but not the insulin or alpha7-nAChR receptors, abrogated the effect of Abeta40 on GABA(A)alpha6 protein expression and current. Furthermore, the expression of GABA(A)alpha6 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 Abeta40 into the cerebellum reversed this effect, and the application of p75(NTR) blocking antibody abolished the effects of Abeta40 on cerebellum morphology in APP(-/-) mice. Our results suggest that low concentrations of Abeta40 play a role in regulating CGN maturation through p75(NTR).


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CRRD ID: 10041036
Created: 2015-05-08
Species: All species
Last Modified: 2015-05-08
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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.