Both the immune system and the central nervous system continuously surveil the environment and make on-demand adjustments to maintain homeostasis. During responses to both physiological and pathophysiological states, specific cell types and states in the nervous and immune systems are involved in behavior and disease.

Alzheimer’s disease (AD) is a currently incurable neurodegenerative disorder, with complex pathology and progressive dementia. Extracellular amyloid-β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks in AD. The regional progression of brain atrophy in AD highly correlates with tau accumulation and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent of the adaptive immune response in the presence of Aβ or Tau pathology. The contribution of the adaptive immune response to neurodegeneration and its interaction with innate immunity remains unknown. Our research first demonstrated that the adaptive immune response is involved in Tau-mediated neurodegeneration and cognitive decline. Those findings answer a fundamental question of how does Tau aggregation lead to regional neuronal death. A better understanding of the specific roles of both the innate and adaptive immune system throughout the course of AD pathology, especially during the Tau phase of AD, will likely lead to novel therapeutic intervention strategies for both the pre-clinical as well as clinically symptomatic phase of AD.

My lab focuses on understanding the brain-body interactions in health and disease. Interdisciplinary approaches including, single-cell multi-omics, metabolisms, clarity imaging, in vivo calcium imaging, optogenetics, and in vivo CRISPR gene editing, are applied in understanding the dialogue of brain-immune communication and developing potential therapeutic tools. The major research directions in my lab are 1) decoding the immune responses in Alzheimer’s disease and therapeutics development, 2) deciphering brain-immune interface and brain-body interaction, and 3) understanding neuronal plasticity throughout AD progression.

Carling G, Fan L, Foxe N, Norman K, Wong M, Zhu D, Corona C, Razzoli A, Yu F, Yarahmady A, Ye P, Chen H, Huang Y, Amin S, Sereda R, Lopez-lee C, Zacharioudakis E, Chen X, Xu J, Cheng F, Gavathiotis E, Cuervo A, Holtzman D, Mok S, Sinha S, Sidoli S, Ratan R, Luo W, Gong S, Gan L. Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model. 2024. Neuron. 112. 1-20, PMID: 38328219

AAIC, Kloske C, Tansey M, Wilcock D (Chen X, leading the study of Microglia-mediated T-cell infiltration and reactivity) Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference. 2024. Alzheimer’s and Dementia. PMID: 39692624

AAIC, Kloske C, Bu G, Goate A, Holtzman D (Chen X, leading the study of APOE and immune response in Alzheimer’s Disease) Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference. 2024. Alzheimer’s and Dementia. 20, 5815-6664, PMID: 39031528

Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, Wang C, Bao X, Finn M, Hu H, Shchukina I, Kim M, Yuede C, Kipnis J, Artyomov M, Ulrich J, Holtzman D. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. 2023. Nature. 615, 668-677, PMID: 36890231

Chen X, Holtzman D. Emerging roles of innate and adaptive immunity in Alzheimer’s Disease. 2022. Immunity. 55, 2236-2254, PMID: 36351425

II-Genetic and epigenetic regulations in learning in adult mammalian brain

Cellular diversification is critical for specialized functions of the brain including learning and memory. Single-cell RNA sequencing facilitates transcriptomic profiling of distinct major types of neurons, but the divergence of transcriptomic profiles within a specific neuronal population and their link to function remain poorly understood. Using single cell multi-omics, in vivo calcium imaging, optogenetics, CRISPR knockout, and behavior analyses, I discovered a subpopulation neuron that specifically undergoes transcriptomic plasticity in response to neuronal activity and learning. Those findings answer the fundamental question of how diversification of neurons influences learning and memory and opens an entirely new and exciting direction of research in neuroscience for studying functional diversity in subtypes of neurons in response to environmental changes.

Chen X, Du Y, Broussard J, Kislin M, Yuede C, Zhang S, Dietmann S, Gabel H, Zhao G, Wang S, Zhang X, Bonni A. Transcriptomic mapping uncovers Purkinje neuron plasticity driving learning. 2022. Nature. 605, 722-727, PMID: 35545673

Chen X, Zhang B, Wang T, Bonni A, Zhao G. Robust principal component analysis for accurate outlier detection in RNA-Seq data. 2020. BMC Bioinformatics. 21, 269. PMID: 32600248

Chen X, Chanda A, Ikeuchi Y, Zhang X, Goodman JV, Reddy NC, Majidi SP, Wu DY, Smith

SE, Godec A, Oldenborg A, Gabel HW, Zhao G, Bonni S, Bonni A. Transcriptional regulator SnoN promotes proliferation of cerebellar granule neuron precursors in the postnatal mouse brain. 2019. J Neurosci. 39, 44-62. PMID: 30425119

Smith SE, Chen X, Brier L, Bumstead J, Rensing N, Epstein A, Oldenborg A, Crowley J, Bice

A, Dikranian K, Ippolito J, Haigis M, Papouin T, Zhao G, Wong M, Culver JP, Bonni A.

Astrocyte deletion of α2-Na/K ATPase triggers episodic motor paralysis in mice via a metabolic pathway. 2020. Nature Communication. 11, 6164. PMID: 33268780

Krishnan N, Chen X, Donnelly-Roberts D, Mohler E.G, Holtzman D. M, Gopalakrishnan, S. M. Small molecule phenotypic screen identifies novel regulators of LDLR expression. 2020. ACS Chem Biol.15, 3262-3274. PMID: 33270420

III-Immune signaling in neuronal maturation

I studied the molecular and cellular mechanisms governing neuropsychiatric disorders by using functional subtype-specific neurons derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). I discovered that MeCP2-deficient human ESCs/iPSCs-derived neurons showed aberrant immature action potentials and synaptic transmission. To capture the molecular mechanisms governing neuron electrophysiological maturation at single cell level, I therefore developed electrophysiological recording coupled with single cell transcriptome analysis (Patch-Seq) and revealed a tight link between neuronal maturation and genes involved in ubiquitination, immune function, and oxidative phosphorylation.

Chen X*, Han X, Blanchi B, Guan W, Ge W, Yu YC*, Sun YE*. Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2. 2020. Protein Cell. 12, 639-652. PMID: 32851591 (co-corresponding author)

Chen X, Zhang K, Zhou L, Gao X, Wang J, Yao Y, He F, Luo Y, Yu Y, Li S, Cheng L, Sun YE.

Coupled electrophysiological recording and single cell transcriptome analyses revealed molecular mechanisms underlying neuronal maturation. 2016. Protein Cell. 7, 175-186. PMID: 26883038 (Cover research)

Chen Y, Yu J, Niu Y, Qin D, Liu H, Li G, Hu Y, Wang J, Lu Y, Kang Y, Jiang Y, Wu K, Li S, Wei J, He J, Wang J, Liu X, Luo Y, Si C, Bai R, Zhang K, Liu J, Huang S, Chen Z, Wang S, Chen X, Bao X, Zhang Q, Li F, Geng R, Liang A, Shen D, Jiang T, Hu X, Ma Y, Ji W, Sun YE. Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

2017. Cell. 169, 945-955. PMID: 28525759

Liu H, Chen Y, Niu Y, Zhang K, Kang Y, Ge W, Liu X, Zhao E, Wang C, Lin S, Jing B, Si C, Lin Q, Chen X, Lin H, Pu X, Wang Y, Qin B, Wang F, Wang H, Si W, Zhou J, Tan T, Li T, Ji S, Xue Z, Luo Y, Cheng L, Zhou Q, Li S, Sun YE, Ji W. TALEN-mediated gene mutagenesis in rhesus and cynomolgus monkeys. 2014. Cell Stem Cell. 14, 323-328. PMID: 24529597

Research Accomplishment

-Ten years scientific journey in filling the gap of neuron-immune interactions