| Summary: | 碩士 === 國立陽明大學 === 生命科學系暨基因體科學研究所 === 100 === Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and the primary risk factor for AD is age. Affected individuals suffer from graduated brain damage leading to memory loss and cognitive decline. Extracellular β-Amyloid (Aβ) accumulation and intracellular neurofibrillary tangles are hallmarks of the AD brain. Mutations in amyloid precursor protein (APP) and presenilin1 (PS1) had been identified to cause the elevation of aggregation-prone Aβ peptides, which are toxic to neurons. Moreover, accumulation of Aβ in cellular compartment impairs organelle function, including mitochondrial dysfunction. Huntington's disease (HD) is a neurodegenerative disorder that affects muscle coordination and leads to cognitive decline and emotional problems. The causing defect is the expanded CAG repeat in exon 1 of the Huntingtin (HTT) gene. Mutant Htt (mHTT) aggregates interferes the normal availability of proteins. Neuronal degeneration in the striatum and cortex has been shown in HD, which results in impaired motor function and dementia. Disturbance in energy metabolism is also clinical hallmark of AD and HD. Neuronal activities have high demand on energy; therefore, neurons are extremely sensitive to mitochondrial function decline. Cisd2 is a novel gene with a newly identified function involving mitochondria. Previously, we have demonstrated Cisd2, which is a mitochondrial outer membrane protein, is essential for the integrity of mitochondrial structure and functions. In Cisd2 knockout mice, mitochondrial breakdown and dysfunction was observed and followed by neuron degeneration leading to a premature aging phenotype. In contrast, we have demonstrated recently that overexpression of Cisd2 prolongs healthy lifespan and delays aging in Cisd2 transgenic (TG) mice. In this study, we investigate whether overexpression of Cisd2 can affect the brain pathogenesis and ameliorate the disease phenotype in AD and HD mouse models; this were achieved by crossing the Cisd2 TG mice with the AD mouse model (APPswe/PSEN1dE9) and HD model (R6/2). Our histopathological analysis revealed that there were similar levels of Aβ accumulation and inflammation in the hippocampus and cortex of the double TG mice (Cisd2;APPswe/PSEN1dE9) compared with the AD mice. Interestingly, our results showed that overexpression of Cisd2 can prevent neuronal loss in the hippocampus of the double TG mice. In addition, TEM ultra-structure study indicated that Cisd2 seems to protect against mitochondrial degeneration, and mitigate synaptic loss in the hippocampus of the double TG mice. Importantly, the double TG mice appear to have a higher survival rate leading to an extended lifespan. Moreover, impaired motor functions were improved in the double TG mice compared with the HD mice. These results suggest that Cisd2 has a potential neuroprotective effect that can alleviate the disease phenotype in the AD and HD mice.
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