My current research is to understand physiology of endolysosome and molecular mechanisms whereby pathological changes in endolysosomes contribute to the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD) and HIV-1 associated neurocognitive disorders (HAND). Successful completion of my current research work will allow me to take the next step in pursuing my long-term goal: design novel preventative and therapeutic strategies against those devastating neurodegenerative diseases.
Current research directions include:
- Ion homeostasis of endolysosomes. Endolysosomes are high dynamic organelles that classically viewed as cellular garbage processing center. Endolysosomes are especially important for neuronal functions, because neurons are long-lived post-mitotic cells that lack the ability to discard cellular garbage via cell division and because neurons are extraordinarily polarized cells with extensive processes that require constant membrane trafficking to maintain synaptic plasticity. Endolysosomes are acidic organelles whose acidic pH is maintained by vacuolar ATPase that pumps proton into the lumen of endolysosomes. Beside high concentrations of proton, endolysosomes also contain high concentrations of other ions including calcium and iron that are readily release. We have demonstrated that modifying endolysosome pH affect release of calcium and iron from endolysosomes. Currently, we are determining molecular mechanisms whereby ion homeostasis of endolysosome is maintained and how altered ion homoeostasis of endolysosomes contributes to neurological diseases.
- Role of endolysosomes in the pathogenesis of Alzheimer’s diseases (AD). Brain depositions of amyloid beta (Aβ) and neurofibrilary tangles composed of p-tau are pathological hallmarks of AD. Because Aβ (generated in multivesicular bodies following AβPP internalization) and aggregated p-tau (enclosed in autophagosomes via autophagy) are degraded in acidic endolysosomes, even modest de-acidification can compromise degradation capabilities of endolysosomes resulting in increased intraneuronal accumulation of Aβ and p-tau as well as secreted levels of Aβ and tau. Thus factors that promotes APP internalization and/or de-acidify endolysosomes could contributes to the development of AD. One such factor is elevated levels of plasma LDL. We have demonstrated that when the BBB is leaky, as occurs early in sporadic AD, elevated circulating LDL enters brain parenchyma and is internalized and accumulated in neuronal endolysosomes. Such a process promotes APP internalization, de-acidifies endolysosomes, and contributes directly to the development of pathological hallmarks of AD. On the other hand, factors that inhibit APP internalization and alleviate endolysosome function could protect against the development of AD. One such promising factor is caffeine. We have demonstrated that caffeine is protective against the disruption of BBB in a cholesterol-fed rabbit model of sporadic AD. Thus, caffeine could protect against cholesterol-enriched diet induced AD-like pathology, in part, by limiting the entry of circulating LDL into the brain parenchyma. Furthermore, our recent findings indicate that caffeine protects against AD by blocking APP internalization and alleviating endolysosome functions, and we are currently investigating its underlying mechanisms.
- Role of endolysosome in the pathogenesis of HIV-1 associated neurocognitive disorders (HAND). Combined antiretroviral therapeutics (ART) has greatly increased the life expectancy of HIV-1 infected individuals. But, these people have a 50% prevalence rate of HIV-1 associated neurocognitive disorder (HAND) and increased clinical and pathological manifestations of AD including cognitive problems, increased brain deposition of Aβ, increased levels of p-tau, and disturbed synaptic integrity. Currently, the pathogenesis of HAND remains unclear, and little is known about how AD-like pathology is developed as a result of HIV-1 infection and/or long-term use of ART drugs. Of mechanistic importance, we have shown that HIV-1 transactivator protein (Tat) induces endolysosome de-acidification and increases Aβ generation. Furthermore, we showed that a subset of ART drugs de-acidified endolysosomes and increased Aβ generation. These novel findings have prompted us to test the hypothesis that endolysosome de-acidification, as a result of HIV-1 Tat internalization and/or endolysosome de-acidifying ART drugs, leads to the development of AD-like pathology.