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      Aβ40 modulates GABA(A) receptor α6 subunit expression and rat cerebellar granule neuron maturation through the ERK/mTOR pathway.

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          Abstract

          In addition to their neurotoxic role in Alzheimer's disease (AD), β-amyloid peptides (Aβs) are also known to play physiological roles. Here, we show that recombinant Aβ40 significantly increased the outward current of the GABA(A) receptor containing (GABA(A)α6) in rat cerebellar granule neurons (CGNs). The Aβ40-mediated increase in GABA(A)α6 current was mediated by an increase in GABA(A)α6 protein expression at the translational rather than the transcriptional level. The exposure of CGNs to Aβ40 markedly induced the phosphorylation of ERK (pERK) and mammalian target of rapamycin (pmTOR). The increase in GABA(A)α6 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 Aβ40 on GABA(A)α6 current and expression in CGNs. A pharmacological blockade of the p75 neurotrophin receptor (p75(NTR)), but not the insulin or α7-nAChR receptors, abrogated the effect of Aβ40 on GABA(A)α6 protein expression and current. Furthermore, the expression of GABA(A)α6 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 Aβ40 into the cerebellum reversed this effect, and the application of p75(NTR) blocking antibody abolished the effects of Aβ40 on cerebellum morphology in APP(-/-) mice. Our results suggest that low concentrations of Aβ40 play a role in regulating CGN maturation through p75(NTR).

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          Author and article information

          Journal
          J. Neurochem.
          Journal of neurochemistry
          1471-4159
          0022-3042
          Feb 2014
          : 128
          : 3
          Affiliations
          [1 ] School of Life Sciences, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
          Article
          10.1111/jnc.12471
          24118019
          7a900a8b-e6b0-4c24-9c2d-566b59269d9a
          © 2013 International Society for Neurochemistry.
          History

          APP−/− mice,Aβ40,ERK/mTOR pathway cerebellar granule neurons,GABAAα6 subunit,p75NTR

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