Research in the Li Lab

Our research interest focuses on understanding molecular and epigenetic basis, and circuit-level mechanisms underlying brain aging and Alzheimer's disease (AD). Our aims lie in bridging molecular and epigenetic dysregulation with neural circuit function and early neuropsychiatric symptoms, a critical synthesis often absent in early AD. Focusing on early disease stages before irreversible neurodegeneration, we identify critical intervention windows. By elucidating how molecular and epigenetic dysregulation, circuit dysfunction, and neuroimmune alterations interact during disease progression, our research aims to determine precision therapeutic strategies for preserving cognitive health across the lifespan.

Neural circuit dysfunction and neuropsychiatric symptoms in early Alzheimer's disease

Neuropsychiatric symptoms, including anxiety, depression, apathy, and sleep disturbances, frequently emerge years before AD clinical cognitive decline and may represent critical windows for therapeutic intervention. Yet the neurobiological substrates connecting molecular pathology to these early behavioral changes remain poorly understood. Our work investigates how age- and disease-related molecular alterations precipitate circuit-level dysfunction within specific brain networks that govern mood, motivation, arousal, and social behavior. We employ spatial transcriptomics and related molecular cartography techniques to map gene expression changes across anatomically defined circuits with cellular resolution. Complementing these molecular approaches, we utilize contemporary circuit-mapping technologies, including viral tracing, optogenetics, chemogenetics, and fiber photometry, to causally link specific neural pathways to behavioral phenotypes relevant to neuropsychiatric dysfunction. We combine transcriptomic, epigenomic, proteomic, and metabolomic profiling with advanced structural and functional imaging modalities, electrophysiological recordings, and quantitative behavioral assessments. This multi-scale integration enables us to construct comprehensive regulatory networks that trace molecular events—from chromatin modifications and transcriptional programs to post-translational modifications and metabolic states—through their manifestations in cellular phenotypes, synaptic function, circuit dynamics, and ultimately behavior. By bridging molecular mechanisms with circuit function and behavioral output, our research aims to identify novel therapeutic targets and biomarkers for early intervention in AD, with particular emphasis on alleviating neuropsychiatric burden and potentially slowing disease progression at its earliest stages.

Neuroimmune dysregulation and glial dysfunction in Alzheimer's disease: from gut-brain axis to therapeutic intervention

Despite extensive study, how neuroimmune dysregulation contributes to Alzheimer’s pathogenesis and progression remains unclear. Emerging evidence suggests that immune and metabolic disturbances arise early, well before overt neurodegeneration, and initiate self-sustaining neuroinflammatory cascades that accelerate disease progression. This conceptual framework challenges traditional neuron-centric models of AD and instead positions neuroimmune dysfunction as a primary driver of disease, rather than a secondary consequence of neuronal pathology. Our research program pursues several interconnected objectives. First, we aim to identify early, actionable neuroimmune-based biomarkers that enable detection of pathological processes during preclinical disease stages, when therapeutic intervention may prevent or delay irreversible neuronal loss. Second, we seek to elucidate targetable molecular pathways within neuroimmune signaling networks that can be modulated to alter disease course. This emphasis on early intervention reflects our conviction that successful disease-modifying strategies will require targeting the earliest pathological events rather than addressing downstream consequences of advanced neurodegeneration. Beyond characterizing molecular and cellular immune mechanisms, we place particular emphasis on understanding astrocyte homeostasis and dysfunction in AD pathogenesis. Astrocytes serve as master regulators of brain homeostasis, orchestrating metabolic support, synaptic function, blood-brain barrier integrity, and immune responses. We examine how disease-associated disruptions in astrocytic polarity, metabolic coupling with neurons, calcium signaling, and cellular senescence compromise these critical neuronal support functions. Our work investigates how astrocyte dysfunction leads to synaptic vulnerability, impaired metabolic homeostasis, and accelerated neurodegenerative processes, with particular attention to regional and circuit-specific astrocyte heterogeneity that may underline selective vulnerability patterns in AD. Concurrently, we investigate the emerging role of the gut-brain axis in AD neuroinflammation and progression. Accumulating evidence suggests that peripheral immune activation, microbiome dysbiosis, and intestinal barrier dysfunction contribute to central nervous system inflammation through multiple pathways, including microbial metabolite signaling, systemic immune activation, and vagal nerve communication. We examine how bidirectional gut-brain communication influences disease-associated neuroinflammation, microglial activation states, synaptic remodeling, and protein pathology in AD. This includes investigating how peripheral immune signals modulate central neuroimmune responses and how central pathology reciprocally affects gut physiology and microbiome composition. By dissecting these complex glial-neuronal interactions and gut-brain signaling pathways, our research fundamentally repositions glial cells and peripheral immune systems as active disease initiators and propagators rather than passive responders to neuronal injury. This paradigm shift opens new therapeutic avenues targeting neuroimmune mechanisms at early disease stages, potentially before the window for meaningful intervention has closed.

Selected Publications

Xu K, Zhang Y, Chen Y, Zhu X, Li Y, Lv L, He X, Hu Z, Li Y, Ye M, Jiang D, He Z, Jin W, Li Y, Yu X, Zhang DF, Herrup K, Zheng P, Yao YG, Wu DD, Li J*. ATM deficiency drives phenotypic diversity and Purkinje cell degeneration in a macaque model of ataxia-telangiectasia. Cell Rep Med. 2025 Sep 16;6(9):102355. PMID: 40961921.

Xiong W, Xu K, Sun JK, Liu S, Zhao B, Shi J, Herrup K, Chow HM, Lu L, Li J*. The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease. EMBO J. 2024 Dec;43(23):6001-6031. PMCID: PMC11612450.

Zhang Z, Zhang Y, Yuwen T, Huo J, Zheng E, Zhang W, Li J*. Hyper-excitability of corticothalamic PT neurons in mPFC promotes irritability in the mouse model of Alzheimer's disease. Cell Rep. 2022 Nov 1;41(5):111577. PMID: 36323265.

Xu K, Zhang Y, Xiong W, Zhang Z, Wang Z, Lv L, Liu C, Hu Z, Zheng YT, Lu L, Hu XT, Li J*. CircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis. Nat Commun. 2020 Jul 17;11(1):3594. PMCID: PMC7367861.

Liu S, Wang Z, Chen D, Zhang B, Tian RR, Wu J, Zhang Y, Xu K, Yang LM, Cheng C, Ma J, Lv L, Zheng YT, Hu X, Zhang Y, Wang X, Li J*. Annotation and cluster analysis of spatiotemporal- and sex-related lncRNA expression in rhesus macaque brain. Genome Res. 2017 Sep;27(9):1608-1620. PubMed Central PMCID: PMC5580719.