Shanghai-Edinburgh Ageing Workshop

Biographies of Speakers

Prof.Jianfeng Feng 冯建峰

Dean & Distinguished Professor, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University

Dean, School of Data Science, Fudan University

Biosketch:Professor Feng is Chair Professor at Shanghai National Centre for Mathematic Sciences, Dean of Institute of Science and Technology for Brain-inspired Intelligence and Dean of School of Data Science at Fudan University. He has been developing new mathematical, statistical and computational theories and methods to meet the challenges raised in Brain Science and mental health research. Recently, his research interests are mainly in big data analysis, mining for neuroscience and brain diseases and developing brain-inspired algorithms and theory. He was awarded the Royal Society Wolfson Research Merit Award in 2011, as a scientist ‘being of great achievements or potentials’. He has made considerable contributions on modelling single neurons and neuronal networks, machine learning, and causality analysis with publications on JAMA Psychiatry, Molecular Psychiatry, Nature Human Behaviour, Science Advances, Brain, PNAS, PRL, IEEE TPAMI etc. He has proposed and developed nonlinear causality analysis, and successfully applied it to search the roots in depression, schizophrenia and autism, including the successful treatment of depressions. He was invited to deliver the 2019 Paykel Lecture at the University of Cambridge.

Professor Feng was recognized as one of the Chinese Most Cited Researchers in Neuroscience of 2019 and one of the Chinese Most Cited Researchers in Mathematics of 2020 and 2021 by Elsevier. He was also named the 2020 World’s Top 2% Scientists by Stanford University.

Prof.Tara Spires-Jones

Personal Chair of Neurodegeneration, Deputy Director Centre for Discovery Brain Sciences, School of Biomedical Sciences, University of Edinburgh. UK Dementia Research Institute Group Leader

Biosketch:Tara Spires-Jones’ research focuses on the mechanisms and reversibility of neurodegeneration in Alzheimer’s disease, other degenerative brain diseases, and ageing. Working with a vibrant group of researchers, she is trying to understand why synapses and neurons become dysfunctional and die in these diseases to develop effective therapeutic strategies. Her work has shown that soluble forms of the pathological proteins amyloid beta and tau contribute to synapse and neurodegeneration (Koffie et al 2009 PNAS, de Calignon et al 2010 Nature), and that lowering levels of these proteins can prevent and reverse phenotypes in model systems (Santacruz et al 2005 Science, Spires-Jones et al 2009 Neurobiol Dis). Her group has discovered that pathological forms of tau spread through the brain via synaptic connections (de Calignon et al Neuron 2012, Pickett et al 2017 Synapse). Working with the Lothian Birth Cohorts 1936, her group has also started to uncover why some people are resilient to cognitive decline during ageing (Henstridge et al 2016 Acta Neuropath Comms, King et al 2023 Alz&Dem). Further, she has pioneered high-resolution imaging techniques in human post-mortem brain and found evidence that pathological proteins accumulate in synapses in human disease (Koffie et al 2012 Brain, Kay et al 2013 Nature Protocols, Colom-Cadena, Davies et al Neuron 2023;). Tara Spires-Jones has published over 100 peer reviewed papers which have been cited over 20,000 times.

In addition to her research, Prof Spires-Jones is passionate about communicating scientific findings to the public and policy makers; increasing the rigour and reproducibility in translational neuroscience; promoting inclusivity and diversity in science; and supporting career development of neuroscientists. She is President of the British Neuroscience Association (2023-2025) and is founding editor of the translational neuroscience journal Brain Communications. She was also a founding member of the FENS-Kavli Network of Excellence, which works to promote the future of European Neuroscience.

Presentation Title:Imaging synaptic pathology in neurodegenerative diseases

Abstract：Synapse loss represents the strongest neuropathological correlate of the progressive cognitive decline observed in Alzheimer’s Disease (AD). Although disease-associated loss of synapses has been documented for decades, we have yet to understand fully how this process initiates and progresses throughout the brain. Indeed, emerging evidence implicates microglia and astrocytes in synaptic degeneration; however, attempting to descriptively characterise their involvement via standard microscopy presents a major challenge due to the diffraction limit of light (250-300 nm) existing beyond the average synapse size. In our group, we have implemented a range of imaging techniques allowing us to study synapses at the mesoscale. This provides us the ability to perform comprehensive analysis of multiple brain regions on a larger scale than that permitted by nanoscale techniques, such as electron microscopy (EM). This includes the technique of array tomography (AT), which circumvents the diffraction limit of light via the physical sectioning of tissue into ribbons of 70 nm contiguous segments. These segments are Immunostained and imaged sequentially at high resolution before being computationally reconstructed into z-stacks. AT, when coupled with other imaging modalities, such as EM and conventional immunohistochemistry (IHC), provides a powerful experimental method for investigating synapse loss in ageing and disease.

In our group, we have observed reversible synapse degeneration in the oligomeric halo surrounding amyloid-b (Ab) plaques in mouse models. Furthermore, we have evidence linking two prominent AD-associated risk genes, APOE4 and CLU, to synapse loss. We have also observed that synapses appear to be ingested by both microglia and astrocytes in human AD brain tissue. More recently, we have incorporated sub-diffraction limit microscopy to provide evidence of oligomeric tau as a potential culprit in the progression of pathology throughout the AD brain via trans-synaptic spread. Understanding synapse degeneration— and on a wider scale, how this interacts with changes associated with the ageing process—will provide an important foundation for the development of disease-modifying therapeutics for Alzheimer’s Disease.

Prof.Zhenyu Ju 鞠振宇

Professor, Jinan University

Biosketch:Dr Zhenyu Ju is a professor at Jinan University in Guangzhou, China, where he directs the Institute of Aging and Regenerative Medicine. Prof. Ju obtained his doctor degree in 2007 at Hannover Medical School. After that, he joined Chinese Academy of Medical Sciences (CAMS, 2007-2011) as an associate professor, and started his professorship at Hangzhou Normal University (2011-2016). In 2016, Prof. Ju moved to Jinan University. Currently his research interest focuses on molecular mechanisms of stem cell and organ aging and related diseases using animal models. His research achievements include: Elucidating the endogenous molecular mechanisms of telomere shortening in stem cell senescence; Stem cell function and homeostasis affected by telomere shortening via increased inflammatory cytokines in blood circulation; The interaction between telomere damage and abnormal energy metabolism. In addition, his lab is developing therapeutic approaches for treating aging-related diseases. Prof. Ju published series of highly influential papers, including in Cell, Nature Genetics, Nature Medicine, Hepatology, Nature Communications, Cell Reports and Circulation Research.

Presentation Title:A Glimpse on Stem Cell and Organ Aging: the Common & Distinct Mechanisms

Abstract:Stem cell aging and organ dysfunction in the elderly underlie the onset and development of aging and age-related diseases. Common and distinct mechanisms drive the age-related (patho-)physiological changes, thus it is crucial to holistically recognize and understand the differences among these factors for a better intervention of the aging process. Here we have investigated the causes of aging in representative tissues and organs with high-/low-turnover rate, and identified several important targets and mechanisms related to telomere and protein homeostasis, immunometabolic remodelling, and epigenetic changes, during aging.

By elucidating that the m5C modification of TERC regulates telomerase activity, and the Dcaf11-Zscan4-Kap1-mediated ALT mechanism, respectively, we identified telomerase-dependent and independent mechanisms that regulate age-associated homeostasis. We also identified the role of the deacetylase SIRT6 and the E3 ligase TRIM31 in HSC aging, followed by the elucidation of the roles of CHOP and EVA1a in stem cell aging and regeneration. The metabolic regulation of the PGC1a-NAD+ axis has been demonstrated in many important target organs such as heart, brain and liver, paving the way for the development of anti-aging therapeutic strategies. In the context of chronic inflammation, we have found that cGAS deficiency promotes inflammation and accelerates cardiac aging.

Moreover, intervention studies targeting these specific candidates showed a great promise to realize healthy aging. MDL-800, a specific SIRT6 agonist, successfully attenuated hematopoietic stem cell aging and inflammation in the aging mouse cohort. The NAD+ precursor β-NMN, which effectively improved the function of vital organs such as brain, intestine, and heart in late life. In addition, LINE1 inhibitors significantly attenuated SASP secretion and thereby ameliorating the inflammatory phenotype in CMML mouse models.

Together, we elucidate the common and distinct mechanisms that drive stem cell and organ aging. These studies provide new insights for mechanistic studies of aging and age-related diseases.

Dr. Simon R. Cox

Director, Lothian Birth Cohorts. Sir Henry Dale Fellow, Psychology Department, University of Edinburgh

Biosketch:Simon Cox is a Sir Henry Dale Fellow at the University of Edinburgh, where he directs the Lothian Birth Cohorts (LBCs) – two longitudinal studies of ageing that follow community-dwelling older adults born in 1921 and 1936. He completed his MA (Hons) at the University of St Andrews, spent some time in industry as a research project manager, before returning to academic to complete his MSc and PhD at the University of Edinburgh. He has worked with the LBCs for fifteen years, and became study director in 2020, where he and his team aim to understand how and why some people’s brains and cognitive functions age differently to others. His research has contributed to the fundamental characterization of brain and cognitive ageing, as well as their potential determinants, mechanisms, and functional/clinical sequelae. His investigations span blood-borne biomarkers, genetic and epigenetic factors, early-life, and malleable lifestyle and environmental factors using diverse methods and datasets from across the life course.

Presentation Title:Overview of the work in the Lothian Birth Cohorts Group

Abstract:I will provide a short summary of the Lothian Birth Cohorts of 1921 and 1936, and some of the recent findings and ongoing investigations into brain, cognitive and other aspects of ageing. These broadly span i) environmental/malleable lifestyle factors, ii) multi-omics, and iii) neuroimaging.

Prof.Shi-Qing Cai 蔡时青

Researcher, Institute of Neuroscience, Chinese Academy of Sciences

Biosketch:Prof Shi-Qing Cai obtained his PhD degree from Shanghai Institute of Plant Physiology & Ecology, Chinese Academy of Sciences, and did his postdoctoral training at Robert Wood Johnson Medical School, Rutgers University. His postdoctoral work mainly focused on the oxidative regulation of potassium channels in the aging nervous system. He joined Institute of Neuroscience, Chinese Academy of Sciences, in 2009. Currently, his study aims to understand 1) the neural basis of healthy aging (Yin & Liu et. al. Journal of Neuroscience 2014, Yin & Gao et. al. Nature 2017, Yuan et. al. Nature 2020); 2) the mechanism underlying ion channel biogenesis including folding, assembly and trafficking (Chen et. al. Journal of Neuroscience 2015, Li et. al. Molecular Cell 2017, Jiang et. al. Nature Communications 2018).

Presentation Title:Neural Basis of Age-Related Behavioral Decline

Abstract:Aging is accompanied with behavioral and cognitive decline. The neural basis of age-related behavioral decline is largely unclear. We report that serotonin (5-HT) and dopamine (DA) level decrease with age in C. elegans. The reduction results in deterioration of some important behaviors, including pharyngeal pumping, food-induced slowing responses, and male mating. Longevity manipulations differentially affect the age-related decline in neuronal level of 5-HT/DA and dietary restriction preserves healthy behaviors in aged worms partially by sustaining a high 5-HT/DA level. Furthermore, we find that C. elegans isolates show diverse lifespan and age-related decline in mating virility, pharyngeal pumping, and locomotion. DNA polymorphisms in a novel peptide-coding gene, named regulatory-gene-for-behavioural-ageing-1 (rgba-1), and a neuropeptide receptor gene npr-28 influence the rate of age-related decline of the worm mating behaviour, suggesting that natural variation in neuropeptide-mediated glia-neuron signalling modulates ageing rate. In addition, through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing C. elegans, we identify 59 genes as potential ageing modulators.

Among these modulators, two neuronal epigenetic readers BAZ-2 and SET-6 accelerate behavioural deterioration in C. elegans by repressing the expression of nuclear-encoded mitochondrial proteins. The mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer’s disease. Ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent bodyweight gain and prevents cognitive decline in ageing mice. Taken together, these findings have unravelled conserved neuronal mechanism underlying healthy ageing, suggesting possible ways to achieve healthy ageing.

Biographies of Speakers

Dr.Donncha Mullin

PhD clinical fellow at. Alzheimer’s Scotland Dementia Research Centre, Centre for Clinical Brain Sciences, Division of Psychiatry, University of Edinburgh

Biosketch:Dr Donncha Mullin is a Psychiatry trainee and exercise enthusiast, having qualified first as a Physiotherapist before studying Medicine. He can be found running in the hills of Scotland but is native to Ireland. Dr Mullin has recently completed his 3-year PhD Clinical Fellowship at the University of Edinburgh and is now working full-time as a clinician in Old Age Psychiatry in the South-East of Scotland. He plans to undertake a post-doctorate once he has more clinical time completed.

Presentation Title:Motoric Cognitive Risk: Epidemiology of a Walking Speed-Based Syndrome to Predict Dementia

Abstract:Dementia is a huge global health challenge without a cure. Identifying the early stages enables the implementation of risk-modifying interventions when they may be most effective. Slow gait speed and self-reported cognitive complaints are among the earliest findings reported in the preclinical stage of dementia. The Motoric Cognitive Risk (MCR) syndrome is a high-risk predementia state combining objective slow gait speed and subjective cognitive complaint in independent, dementia-free individuals. This presentation will discuss my research on the association between MCR and dementia using meta-analysis and several epidemiological approaches in a Scottish cohort of community-dwelling older adults.

The findings of my research represent a significant advancement in our understanding of MCR prevalence, risk factors, predictive ability, and trajectories. By improving our understanding of this high-risk predementia state, this work brings us closer to the ultimate goal of intervening early in the lifecourse to reduce the number of people living with dementia.

Prof.Guang-Hui Liu 刘光慧

Researcher and Fellow, Chinese Academy of Medical Sciences

Biosketch:Guang-Hui Liu is a researcher and a fellow of the Chinese Academy of Medical Sciences. He is a fellow of the International Union of Physiological Sciences and serves as the Deputy Director of the Academic Committee at the Institute of Zoology, Chinese Academy of Sciences. He is also the Deputy Director of the State Key Laboratory of Membrane Biology, Director of the Stem Cell and Regenerative Medicine Science Data Center at the Chinese Academy of Sciences, Vice President and Director of the Academic Committee at the Beijing Institute of Stem Cell and Regenerative Medicine, and the principal investigator of the Creative Research Groups project funded by the National Natural Science Foundation of China.

He has been engaged in research on aging and medicine for a long time. He has published over a hundred articles as the corresponding author in journals such as Cell, Nature, and Science, with a total citation count of over ten thousand. He holds 33 authorized patents, including 2 PCT patents. His representative achievements have been selected as one of the Top Ten Scientific Advances in China (2020), Top Ten Advances in Life Sciences in China (2018; 2020), Elsevier Highly Cited Researchers in China (2020-2022).

Currently, he serves as a founding council member of the International Academy for Health & Lifespan Research, President of the Aging Cell Research in the Chinese Society for Cell Biology, Chief Editor of Life Medicine, Associate Editor of Protein & Cell, editorial board member of China Science Life Science, Cell Reports, Aging Cell, and PLoS Biology. He has been awarded the National Innovation Award, the Outstanding Scientific and Technological Achievement Award issued by Chinese Academy of Sciences, the China Youth Science and Technology Award Special Award, the Tan Jiazhen Life Science Innovation Award, the Xplorer Prize, and the first prize for the Overseas Chinese Contribution Award.

Presentation Title:Programming and Reprogramming of Aging

Abstract:Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.

Prof.Jintai Yu 郁金泰

Professor and Vice Director, Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Fudan University

Biosketch:Dr. Jin-Tai Yu is a full Professor of Neurology and the Vice Director of the Institute of Neurology, WHO Collaborating Center for Research and Training in Neurosciences, Fudan University, Shanghai, China. He also directs the Memory Clinic and Cognitive Ward of the Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University. He obtained his MD degree from Qingdao University and his PhD degree from Ocean University in China. He went on to his postdoctoral study in dementia in the Department of Neurology at UCSF. He then worked as an associate specialist of neurology at the UCSF Medical Center. Currently, he is focusing on basic and clinical research for Alzheimer’s disease and related dementia, and the PI of several national grants on dementia. He has published more than 100 research papers in Lancet Neurology, Alzheimer’s & Dementia, Science Advances, Biological Psychiatry, Movement Disorders, Neurology, et al. that have been cited more than 17000 times by peer scientists in the field. He is currently the Editor-in-Chief of Brain Disorders, Associate Editor-in-Chief of Annals of Translational Medicine, Senior Editor of Journal of Alzheimer’s Disease, Editor of Journal of Prevention of Alzheimer’s Disease, and Editor of American Journal of Neurodegenerative Disease.

Presentation Title:Association of Biological Age with Health Outcomes and its Modifiable Factors

Abstract:Identifying the clinical implications, modifiable and unmodifiable factors of aging requires the measurement of biological age (BA) and age gap. Leveraging the biomedical traits involved with physical measures, biochemical assays, genomic data, and cognitive functions from the healthy participants in the UK Biobank, we establish an integrative BA model consisting of multi-dimensional indicators. Accelerated aging (age gap > 3.2 years) at baseline is associated incident circulatory diseases, related chronic disorders, all-cause and cause-specific mortality. We identify 35 modifiable factors for age gap, where pulmonary functions, body mass, hand grip strength, basal metabolic rate, and estimated glomerular filtration rate show the most significant associations. Genetic analyses replicate the associations between age gap and health-related outcomes and identify CST3 as an essential gene for biological aging, which is highly expressed in brain and is associated with immune and metabolic traits. Our study profiles the landscape of biological aging and provides insights into the preventive strategies and therapeutic targets for aging.

Kristjan Holt

Wellcome Trust PhD Student, Spires-Jones/Hardingham Labs, Centre for Discovery Brain Science, School of Biomedical Sciences, University of Edinburgh

Biosketch:Kristjan Holt is a second-year Wellcome Trust funded PhD student, working within the Spires-Jones and Hardingham groups at The University of Edinburgh. After obtaining his undergraduate BSc in Biomedical Sciences (Anatomy) at The University of Aberdeen in 2017, Kristjan moved to Edinburgh where he attained his postgraduate MScR in Integrative Neuroscience with distinction. As part of his MScR, Kristjan contributed to research within the Spires-Jones group, working closely with Professor Tara Spires-Jones and senior postdoctoral associate, Dr Declan King; his project involving the use of the specialist high-resolution microscopy technique—array tomography (AT)—to investigate whether measures of synaptic resilience are linked with retained cognitive function during ageing. Working as part of a collaborative team using donated post-mortem tissue from the well-characterised Lothian Birth Cohort (1936) who provide valuable longitudinal measures of cognition over the lifespan this study combined AT with transcriptomic and descriptive histological analyses; comparing these data against age-matched donors who died with Alzheimer’s Disease (AD). This work is published in Alzheimer’s & Dementia (King et al., 2023).

Kristjan’s current work as part of his PhD project involves the investigation of microglial contribution to the seeding and progression of amyloid-b (Ab) in the brain as part of AD. This work involves the well-characterised murine model of amyloidopathy, ‘APP/PS1’, crossed with the recently developed model of microglial ablation, ‘FIRE’. The FIRE mice, developed by the collaborative effort of multiple groups at The University of Edinburgh, harbour a CRISPR-mediated deletion of a 337 bp super-enhancer sequence within the Csf1r gene, resulting in a failure of microglia to mature within the brain. By crossing these mice with APP/PS1 counterparts, Kristjan aims to phenotypically characterise the resultant offspring, ‘FIRE x APP/PS1’, which are observed to develop Ab pathology in the absence of microglia.

Presentation Title:Synaptic Resilience is Associated with Maintained Cognition During Ageing

Abstract:Cognitive decline is described as one of the most feared aspects of the ageing process. As well as cognitive decline being common during ageing, age is the most important risk factor for Alzheimer's disease (AD). Region-specific synapse loss has been observed in post-mortem studies of aged human brain and in animals similar changes are associated with cognitive decline.

In AD, synapse loss also correlates strongly with cognitive decline, and we have observed that synaptic accumulation of pathological forms of amyloid beta (Aβ) and tau are associated with synapse loss in AD brain. In model systems, we and others have observed that altered synaptic signalling downstream of Aβ and tau cause cognitive decline in ageing animals. Several well-characterized cohorts have been used to study brain changes associated with cognitive ageing including the Religious Orders Study, Rush Memory and Ageing Project and the Cognitive Function and Ageing Studies. These and other studies highlight the importance of different responses to pathological protein accumulation and both the genetic and environmental risk factors associated with age-related cognitive decline. However, significant gaps in knowledge remain including understanding brain changes associated with cognitive change over a large portion of the lifetime (starting in childhood) and detailed analysis of synapse density and protein composition at high resolution previously prevented by technical limitations.

Here we addressed some of these knowledge gaps using a combination of advanced techniques and brain donations from the participants in the Lothian Birth Cohort 1936 (LBC1936), a well-characterized cohort studying cognitive ageing. LBC1936 participants took a version of the Moray House Test No. 12 (MHT) of general intelligence at age 11 and have participated since the age of 70 in a longitudinal study of cognitive ageing. Using brain samples and induced pluripotent stem cell (iPSC) derived neurons derived from this unique cohort alongside brain tissue donated from middle-aged people who died from non-neurological conditions, and people who died with AD, we conducted an in-depth study of synaptic pathology and molecular composition to study synaptic changes associated with resilience to cognitive decline in ageing.

Prof.Bo Peng 彭勃

Professor and Assistant Director, Institute for Translational Brain Research, Fudan University

Biosketch:Prof Bo Peng is a professor and assistant director at Institute for Translational Brain Research, Fudan University. He obtained his bachelor degree of biotechnology in 2008 at Huazhong University of Science and Technology. He then studied neurophysiology at Institute of Neuroscience at Chinese Academy of Sciences from 2008 to 2011. After that, he investigated retinal degenerative disorders at The University of Hong Kong and obtained his Ph.D. degree in neuroscience at 2015. After that, Dr. Bo Peng joined Shenzhen Institutes of Advanced Technology at Chinese Academy of Sciences as an associate professor and established his own lab. In 2019, Dr. Bo Peng moved to Fudan University.

Dr. Bo Peng's laboratory is mainly focusing on understanding how microglia turnover in physiological and pathological conditions. In addition, his lab is developing therapeutic approaches for treating CNS disorders. Dr. Bo Peng published series of corresponding author papers, including in Nature Neuroscience, Neuron, Nature Communications, Cell Reports and eLife.

Presentation Title:Repopulation and Replacement: the Philosophy of Microglia

Abstract:Microglia undergo turnover (including cell death and regeneration) throughout the lifespan. Newborn microglia rapidly replenish the whole brain after selective elimination of most microglia (>99%) in adult mice. The origin of these repopulated microglia has been hotly debated. We investigated the origin of repopulated microglia and demonstrated that all repopulated microglia were derived from the proliferation of the few surviving microglia (<1%).

Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia-associated disorders. However, some attempts have failed due to low replacement efficiency, such as with the traditional bone marrow transplantation approach. Based on our understanding in microglial repopulation, we develop three efficient strategies for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.

On the other hand, if microglial debris is not removed in a timely manner, accumulated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We find that although microglia can phagocytose microglial debris in vitro, the territory-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization and degraded by noncanonical autophagy.

Together, we elucidated mechanisms of microglia turnover and developed novel therapeutic approaches for neurological disorders.