Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer’s disease

作者：Weilin Liu, Jianhong Li, Minguang Yang, Xiaohua Ke, Yaling Dai, Huawei Lin, Sinuo Wang, Lidian Chen, Jing Tao · 发表于：Alzheimer s Research & Therapy · 年份：2022 · DOI：10.1186/s13195-022-00994-w · 被引用次数：58 · 研究领域：Memory and Neural Mechanisms、Alzheimer's disease research and treatments、Neuroscience and Neuropharmacology Research

BACKGROUND: The degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer's disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models. METHODS: Novel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aβ plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively. RESULTS: We found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in AP...