Description

The most common neurological disease is Alzheimer's disease (AD), characterized by cognitive impairment due to a progressive loss of cerebral neurons, which is affected mostly in elderly people (Wang, et al., 2019). Recent studies have indicated that endolysosomal dysfunction likely plays an important role in the early phases of the pathogenesis of neurodegenerative diseases such as AD. Whereas mitochondria play an essential role in aging, cancer, diabetes, and neurodegenerative diseases. Mutant and aberrant mitochondrial proteins alter neuronal function and cell death structurally and functionally (Malik, et al., 2019. Reddy, et al., 2009). In this experiment, I will be using primary embryonic neurons from the PSAPP mouse that models AD to define the molecular and cellular pathogenic mechanisms of Mitochondria Membrane Potential (MMP). I hypothesize that endolysosomal and mitochondrial structures and functions are significantly impacted in the PSAPP neurons, contributing to neurodegeneration in this AD mouse model. I will establish primary cortical neuronal cultures from both the WT and the PSAPP embryos. I will use LysoTraker to measure lysosomal transport. To study mitochondrial function, I will use a ratiometric dye JC9 to measure the mitochondrial membrane potential (MMP). Live cell imaging of axons/neurites will be carried out to quantitate LysoTracker and JC9 signals. The results will be used to compare PSAPP with WT control neurons. To validate my results, I will also measure lysosomes and mitochondria in neuronal progenitor cells (NPCs) from healthy controls and AD patients. Specifically, I will quantitate and analyze: The size, motility, and activity of lysosomes in both healthy and disease neurons/cells. The size, motility, and activity of mitochondria in both healthy and diseased neurons/cells. The results collected will be used to establish: Endocytic trafficking is defective in disease neurons/cells – an essential cellular process that transports proteins, hormones, growth factors, receptor tyrosine kinases, and lipids. Mitochondria dynamics and functions are altered in disease neurons/cells – the powerhouse to support all essential cellular functions and dysfunctional mitochondria have been implicated in many neurodegenerative diseases. My study is expected to demonstrate that endolysosomal/mitochondrial dysfunction that occurs early in neurodegenerative disorders contributes critically to the pathogenesis of these diseases.