Neuroimmunology, Alzheimer’s Disease Research

 I-Neuron-immune interaction in Alzheimer’s 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. 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.

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

Highlighted by Nature and Nature aging

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. 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

Those findings 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-responding authors)

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