Open AccessActivation of GSK ‐3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats
Author(s) -
Wang Yue,
Tian Qing,
Liu EnJie,
Zhao Li,
Song Jie,
Liu XinAn,
Ren QingGuo,
Jiang Xia,
Zeng Juan,
Yang YuTao,
Wang JianZhi
Publication year - 2017
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13262
Subject(s) - nucleus basalis , cholinergic , cholinergic neuron , endocrinology , medicine , acetylcholine , basal forebrain , gsk 3 , wortmannin , acetylcholinesterase , biology , chemistry , microbiology and biotechnology , kinase , signal transduction , biochemistry , pi3k/akt/mtor pathway , enzyme
The cholinergic impairment is an early marker in Alzheimer's disease ( AD ), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse‐3 ( GSK ‐3) activation on the cholinergic homoeostasis in nucleus basalis of Meynert ( NBM ) and frontal cortex, the cholinergic enriched regions. We activated GSK ‐3 by lateral ventricular infusion of wortmannin ( WT ) and GF ‐109203X ( GFX ), the inhibitors of phosphoinositol‐3 kinase ( PI 3‐K) and protein kinase C ( PKC ), respectively, and significantly decreased the acetylcholine ( AC h) level via inhibiting choline acetyl transferase (Ch AT ) rather than regulating acetylcholinesterase ( AC hE). Neuronal axonal transport was disrupted and Ch AT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, Ch AT expression decreased in NBM attributing to cleavage of nuclear factor‐κB/p100 into p52 for translocation into nucleus to lower Ch AT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK ‐3 and rescued by simultaneous administration of LiCl or SB 216763, inhibitors of GSK ‐3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients.