Journal Article

Synaptosomal Mitochondrial Dysfunction in 5xFAD Mouse Model of Alzheimer's Disease

Shao, Muming, Li, Lin, Guo, Lan, Wang, Lu, Du, Yifeng, Lu, Lin, Beck, Simon J., Du, Heng, Sun, Huili, Ramachandran, Janani

2016

Overview

Brain mitochondrial dysfunction is hallmark pathology of Alzheimer's disease (AD). Recently, the role of synaptosomal mitochondrial dysfunction in the development of synaptic injury in AD has received increasing attention. Synaptosomal mitochondria are a subgroup of neuronal mitochondria specifically locating at synapses. They play an essential role in fueling synaptic functions by providing energy on the site; and their defects may lead to synaptic failure, which is an early and pronounced pathology in AD. In our previous studies we have determined early synaptosomal mitochondrial dysfunction in an AD animal model (J20 line) overexpressing human Amyloid beta (Aβ), the key mediator of AD. In view of the limitations of J20 line mice in representing the full aspects of amyloidopathy in AD cases, we employed 5xFAD mice which are thought to be a desirable paradigm of amyloidopathy as seen in AD subjects. In addition, we have also examined the status of synaptosomal mitochondrial dynamics as well as Parkin-mediated mitophagy which have not been previously investigated in this mouse model. In comparison to nontransgenic (nonTg mice), 5xFAD mice demonstrated prominent synaptosomal mitochondrial dysfunction. Moreover, synaptosomal mitochondria from the AD mouse model displayed imbalanced mitochondrial dynamics towards fission along with activated Parkin and LC3BII recruitment correlating to spatial learning & memory impairments in 5xFAD mice in an age-dependent manner. These results suggest that synaptosomal mitochondrial deficits are primary pathology in Aβ-rich environments and further confirm the relevance of synaptosomal mitochondrial deficits to the development of AD.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Age / Aging - pathology / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer Disease - physiopathology / Alzheimer's disease / Alzheimers disease / Amyloid beta-Peptides - metabolism / Analysis / Animal models / Animals / Attention / Autophagy / Axons - metabolism / Biology and Life Sciences / Brain / Brain research / Cells, Cultured / Cognitive impairment / Complications and side effects / Disease Models, Animal / Energy Metabolism / Genetic aspects / Hospitals / Medicine and Health Sciences / Memory / Mice / Mice, Transgenic / Microtubule-Associated Proteins - metabolism / Mitochondria / Mitochondria - metabolism / Mitochondrial diseases / Mitochondrial DNA / Mitochondrial Dynamics / Mutation / Neurodegenerative diseases / Neurons - metabolism / Neurosciences / Parkin protein / Parkinson's disease / Parkinsons disease / Pathogenesis / Pathology / Protein Transport / Recruitment / Research and Analysis Methods / Risk factors / Rodents / Social Sciences / Spatial discrimination learning / Spatial Learning / Spatial memory / Studies / Synapses / Synaptogenesis / Synaptosomes - metabolism / Ubiquitin-Protein Ligases - metabolism