甲基枸杞碱
医学
化学
尼古丁
药理学
神经保护
神经退行性变
内科学
烟碱乙酰胆碱受体
神经炎症
内分泌学
作者
Meilin Wu,Clifford Z. Liu,Erika A. Barrall,Robert A. Rissman,William J. Joiner
标识
DOI:10.1523/jneurosci.0494-21.2021
摘要
α7 nAChRs are widely expressed in the brain where they promote fast cholinergic synaptic transmission and serve important neuromodulatory functions. However, their high permeability to Ca2+ also predisposes them to contribute to disease states. Here, using transfected HEK-tsa cells and primary cultured hippocampal neurons from male and female rats, we demonstrate that two proteins called Ly6h and NACHO compete for access to α7 subunits, operating together but in opposition to maintain α7 assembly and activity within a narrow range that is optimal for neuronal function and viability. Using mixed gender human temporal cortex and cultured hippocampal neurons from rats we further show that this balance is perturbed during Alzheimer’s disease due to amyloid beta-driven reduction in Ly6h, with severe reduction leading to increased phosphorylated tau and α7-mediated neurotoxicity. Ly6h release into human cerebrospinal fluid is also correlated with Alzheimer’s disease severity. Thus, Ly6h links cholinergic signaling, amyloid beta and phosphorylated tau and may serve as a novel marker for Alzheimer’s disease progression. SIGNIFICANCE STATEMENT: One of the earliest and most persistent hypotheses regarding Alzheimer’s disease attributes cognitive impairment to loss of cholinergic signaling. More recently, interest has focused on crucial roles for amyloid beta and phosphorylated tau in Alzheimer’s pathogenesis. Here we demonstrate that these elements are linked by Ly6h and its counterpart, NACHO, functioning in opposition to maintain assembly of nicotinic acetylcholine receptors (nAChRs) within the physiological range. Our data suggests that amyloid beta shifts the balance away from Ly6h and toward NACHO, resulting in increased assembly of Ca2+-permeable nAChRs and thus a conversion of basal cholinergic to neurotoxic signaling.
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