Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-β and tau in a mouse model of Alzheimer’s disease

生物 疾病 TRPV1型 阿尔茨海默病 神经科学 基因剔除小鼠 瞬时受体电位通道 医学 淀粉样蛋白(真菌学) 受体 细胞生物学 遗传学 内科学 植物
作者
Juyong Brian Kim,Siyoung Lee,Jaekyoon Kim,Sangwoo Ham,Jung Han Yoon Park,Seungbong Han,Yong‐Keun Jung,Insop Shim,Jung‐Soo Han,Ki Won Lee,Jiyoung Kim
出处
期刊:Human Molecular Genetics [Oxford University Press]
卷期号:29 (2): 228-237 被引量:30
标识
DOI:10.1093/hmg/ddz276
摘要

Abstract The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer’s disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/−) and knockout (TRPV1−/−) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals’ memory function, hippocampal Ca2+ levels and amyloid-β (Aβ) and tau pathologies when they were 12 months old. We found that compared with 3xTg-AD−/−/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aβ and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1−/− mice had better memory function and lower levels of hippocampal Ca2+, Aβ, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aβ, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.
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