粒体自噬
生物
线粒体分裂
线粒体
转基因小鼠
细胞生物学
自噬
MFN2型
DNM1L型
线粒体生物发生
树突棘
转基因
莫里斯水上航行任务
τ蛋白
线粒体融合
神经科学
海马体
阿尔茨海默病
内科学
线粒体DNA
生物化学
海马结构
医学
细胞凋亡
基因
疾病
作者
Ramesh Kandimalla,Maria Mańczak,Jangampalli Adi Pradeepkiran,Hallie Morton,P. Hemachandra Reddy
摘要
Abstract The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer’s disease (AD). Our laboratory reported increased levels of amyloid-beta (Aβ) and phosphorylated Tau (P-Tau) and reported that abnormal interactions between Aβ and Drp1, P-Tau and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in AD. These abnormal interactions result in the proliferation of dysfunctional mitochondria in AD neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in AD. To determine the impact of reduced Drp1 in AD, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/−) mice and generated double mutant (P301LDrp1+/−) mice. In the current study, we assessed the cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology and mitochondrial function and dendritic spines in Tau mice relative to double mutant mice. When compared with Tau mice, double mutant mice did better on the Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA- and protein-level autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared with Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number was reduced and length was increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.
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