title: Aβ40 modulates GABA(A) receptor α6 subunit expression and rat cerebellar granule neuron maturation through the ERK/mTOR pathway.
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).
authors.affiliation: School of Life Sciences, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Zhan
authors.forename: Jin-Jing
authors.initials: JJ
authors.lastname: Yao
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Liu
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Ma
authors.forename: Yan-Ai
authors.initials: YA
authors.lastname: Mei
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D019921:Biotinylation; D015153:Blotting, Western; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C546173:Gabra6 protein, rat; D010446:Peptide Fragments; D020800:Receptor, Nerve Growth Factor; D011963:Receptors, GABA-A; C078592:amyloid beta-protein (1-40); D005680:gamma-Aminobutyric Acid; D058570:TOR Serine-Threonine Kinases
keywords: APP−/− mice; Aβ40; ERK/mTOR pathway cerebellar granule neurons; GABAAα6 subunit; p75NTR