Xuesong Chen

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:       

1. 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.
2. 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.
3. 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. 

Original Peer-reviewed articles:

1. Chen X, Zhang HY, Pavlish K, and Benoit JN. (2005) Effects of chronic portal hypertension on small heat-shock proteins in mesenteric arteries. Am J Physiol 288(4): G616-620.
2. Zhang HY, Shirasawa Y, Chen X, Yu H, and Benoit JN. (2005) Impaired agonist-dependent myosin phosphorylation and decreased RhoA in rat portal hypertensive mesenteric vasculature. Am J Physiol 288(4): G603-608.
3. Wu Zy, Chen XS, Qiu JF, and Cao H. (2005) Role of PGI2 in the formation and maintenance of hyperdynamic circulatory state of portal hypertensive rats. World J Gastroenterol 11(5): 752-755.
4. Chen X, Pavlish K, Zhang HY, and Benoit JN. (2006) Effects of chronic portal hypertension on agonist-induced actin polymerization in small mesenteric arteries. Am J Physiol 290(5): H1915-21.
5. Chen X, Pavlish K, and Benoit JN. (2008) Myosin Phosphorylation Triggers Actin Polymerization in Vascular Smooth Muscle. Am J Physiol 295(5): H2172-7.
6. Chen X, Gawryluk JW, Wagener JF, Ghribi O, and Geiger JD. (2008) Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer’s disease. Journal of Neuroinflammation Apr 3; 5:12
7. Chen X, Lan X, Roche I, Liu R, Geiger JD. (2008) Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum. Journal of Neurochemistry 107(4): 1147-57.
8. Chen X, Ghribi O, and Geiger JD. (2008) Rabbits fed cholesterol-enriched diets exhibit pathological features of inclusion body myositis. Am J Physiol 294(3): R829-35.
9. Chen X, Ghribi O, and Geiger JD. (2010) Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer’s and Parkinson’s disease. Journal of Alzheimer’s Disease 20 Suppl 1:S127-41
10. Masino, S.A., Kawamura, M. Ruskin, D.N., Gawryluk, J., Chen, X., and J.D. Geiger. (2010) Purines and the Anti-Epileptic Actions of Ketogenic Diets. Special Issue on “Purinergic Signaling in Epilepsy”, Open Neuroscience Journal 4: 58-63
11. Prasanthi JRP, Dasari B, Marwarha G, Larson T, Chen X, Geiger JD, and Ghribi O. (2010) Caffeine protects against oxidative stress and Alzheimer’s disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radial Biology and Medicine Oct 15; 49(7): 1212-20
12. Chen X, Wagener JF, Morgan DL, Hui L, Ghribi O, and Geiger JD. (2010) Endolysosome mechanisms associated with Alzheimer’s disease-like pathology in rabbits ingesting cholesterol-enriched diet. Journal of Alzheimer’s Disease 22(4):1289-303
13. Bhatt DP, Chen X, Geiger JD, and Rosenberger TA (2012). A sensitive HPLC-based method to quantify adenine nucleotides in primary astrocyte cell cultures. J Chromatogr B Analyt Technol Biomed Life Sci. 15;889-890:110-5.
14. Hui L, Chen X, Haughey NJ, Geiger JD (2012). Role of endolysosomes in HIV-1 Tat-induced neurotoxicity. ASN Neuro. 20;4(4).
15. Hui L, Chen X, Geiger JD (2012). Endolysosome involvement in LDL cholesterol-induced Alzheimer's disease-like pathology in primary cultured neurons. Life Sci. 91(23-24):1159-68.
16. Hui L, Chen X, Bhatt D, Geiger NH, Rosenberger TA, Haughey NJ, Masino SA, Geiger JD (2012). Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. J Neurochem. Apr 23 (1471-4159)
17. Srivastava S, Kashiwaya Y, Chen X, Geiger JD, Pawlosky R, Veech RL (2012). Microwave irradiation decreases ATP, increases free [Mg²?], and alters in vivo intracellular reactions in rat brain. J Neurochem. 123 (5): 668-75
18. Chen X, Hui L, Geiger NH, Haughey NJ, and Geiger JD (2013) Endolysosome Involvement in HIV-1 Tat-Induced Neuronal Amyloid Beta Production. Neurobiology of Aging Oct; 34(10): 2370-8
19. Morgan DH, Ghribi O, Hui L, Geiger JD, Chen X (2014). Cholesterol-enriched diet disrupts the blood-testis barrier in rabbits. Am J Physiol Endocrinol Metab. 307(12):E1125-30
20. Stevens PR, Gawryluk JW, Hui L, Chen X, Geiger JD (2014). Creatine Protects Against Mitochondrial Dysfunction Associated with HIV-1 Tat-Induced Neuronal Injury. Curr HIV Res. 12(6):378-87
21. Li S, Geiger NH, Soliman ML, Hui L, Geiger JD, Chen X (2015) Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid Beta Precursor Protein Internalization and Amyloid Beta Generation. Journal of Alzheimer’s Disease 47: 73–83
22. Hui L, Geiger NH, Bloor-Young D, Churchill GC, Geiger JD, Chen X. (2015) Release of calcium from endolysosomes increases calcium influx through N-type calcium channels: Evidence for acidic store-operated calcium entry in neurons. Cell Calcium 58(6):617-27
23. Chen X, Tian H, Ghribi O, and Geiger JD (2016) Caffeine blocks cholesterol-enriched diet induced AD-like pathology in rabbits. J Syst Integr Neurosci 2(1): 99-106
24. Chen X, Wagener JF, Ghribi O, Geiger JD. (2016) Role of Endolysosomes in Skeletal Muscle Pathology Observed in a Cholesterol-Fed Rabbit Model of Alzheimer's Disease. Front Aging Neurosci. 2016; 8:129. PMCID: PMC4896918.
25. Soliman ML, Geiger JD, Chen X (2017). Caffeine Blocks HIV-1 Tat-Induced Amyloid Beta Production and Tau Phosphorylation. J Neuroimmune Pharmacol;12(1):163-170
26. Khan N, Datta G, Geiger JD, Chen X (2018) Apolipoprotein E isoform dependently affect Tat-mediated HIV-1 LTR transactivation. J Neuroinflammation. 15(1): 91
27. Ye Y, Hui L, Lakpa KL,Xing Y, Wollenzien H, Chen X, Zhao JX and Geiger JD (2018) Effects of silica nanoparticles on endolysosome function in primary cultured neurons. Can J Physiol Pharmacol 2018 Oct 12 [Epub ahead of print].
28. Hui L, Soliman ML, Geiger NH, Miller NM, Afghah Z, Lakpa KL, Chen X, and Geiger JD (2018). Acidifying endolysosomes prevented LDL-induced amyloidogenesis. Journal of Alzheimer’s Disease (in press)

Reviews:

1. Chen X, Ghribi O, and Geiger JD. (2010) Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer’s and Parkinson’s disease. Journal of Alzheimer’s Disease 20 Suppl 1:S127-41
2. Moderator: James JE, Participants: Chen X, Morelli M, Postuma R, Schwarzschild MA. The putative neuroprotective effects of caffeine. Journal of Caffeine Research. 2011, 1(2): 91-96
3. Chen X, Hui L and Geiger JD (2014). Role of Endolysosomes and Cholesterol in the Pathogenesis of Alzheimer’s Disease: Insights into why Statins might not Provide Clinical Benefit. Austin J Pharmacol Ther. 2 (6).7
4. Chen X, Hui L, Geiger JD (2014) Role of LDL Cholesterol and Endolysosomes in Amyloidogenesis and Alzheimer’s Disease. J Neurol Neurophysiol 5: 236.
5. Chen X, Hui L, Geiger JD (2014) Amyloid Beta Accumulation in HIV-1 Infected Brain: The Role of Altered Cholesterol Homeostasis. Clin Res HIV/AIDS 1(2): 1011.
6. Chen X, Hui L, Soliman ML, Geiger JD (2014). Altered Cholesterol Intracellular Trafficking and the Development of Pathological Hallmarks of Sporadic AD. J Parkinsons Dis Alzheimer Dis. 1(1): 8.
7. Geiger JD, and Chen X (2017). Human Immunodeficiency Virus Transactivator of Transcription–Induced Increases in Depression-like Effects Are Linked to Oxidative Stress (Commentary). Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2(7); 552-553

Book Chapter:

1. Chen, X., Hui, L., and Geiger, J. D. (2012). Adenosine and energy metabolism – relationship to brain bioenergetics, In Adenosine: A Key Link Between Metabolism and Central Nervous System Activity, S. A. Masino, and D. Boison, eds. (New York: Springer).
2. Chen X, Soliman ML, Hui L, Geiger JD (2014). Homeostatic control of adenosine levels and functions in brain, in Homeostatic Control of Brain Function, S. A. Masino, and D. Boison, eds. (Oxford University Press)

Invited talks:

1. “Endolysosome involvement of HIV-1 Tat-induced neuronal amyloid beta production” 2015 Society on Neuroimmune and Pharmacology (SNIP) symposium, Miami, Florida (April 2015)
2. “LDL Cholesterol and Sporadic AD: The Role of Endolysosome Dysfunction” BIT’s 7th Annual World Congress of NeuroTalk-2016, Beijing, China (May 2016)
3. “Endolysosome Involvement of HIV-1 Tat-Induced Neuronal Amyloid Beta Production” The Pathobiology of the Lysosome and Lysosomal Diseases Conference, Cambridge, UK (July 2016)
4. “Endolysosome de-acidification affects the structure and function of endolysosomes as well as their ability to interact with and signal between other intracellular organelles” 2018 Joint meeting by the Society on Neuroimmune and Pharmacology (SNIP) and International Symposium on NeuroVirology (ISNV), Chicago, Illinois (April 2018)

• Ph.D, University of North Dakota
• MD, Medical School of Tongji University, Shanghai, China  
• MS, School of Medicine, Shanghai Jiao Tong University, Shanghai, China