Biology subjects

Lloyd, A. F.

Publications and source records attributed to Lloyd, A. F..

6 recordsLinked to original sources

bioRxiv2026

Glycogen-Dependent Metabolic Reprogramming Regulates Microglial Activation and Dysfunction in Neurodegenerative Disease

Microglia are central regulators of neuroinflammation in Alzheimers disease (AD), yet how metabolic states modulate function remains unclear. Here we show that microglia from the APPNL-G-F mouse model revealed upregulation of glycolytic enzymes coinciding with onset of microglial activation. Surprisingly, this glycolytic shift occurred alongside reduced expression of glucose transporters, suggesting that extracellular glucose may not be the primary fuel source, implicating glycogenolysis as the potential metabolic driver. Consistent with this, significant microglial glycogen accumulation was noted in late disease, when cells exhibited features of metabolic exhaustion and functional impairment. Pharmacological inhibition of glycogenolysis blunted microglia responses to Abeta aggregates and markedly reduced Abeta uptake, confirming a functional role for glycogen metabolism in shaping microglial states. Together, these findings identify glycogen as a central regulator of microglial metabolic health and function, highlighting glycogen homeostasis as a potential therapeutic target for promoting Abeta clearance and preserving protective microglial functions in AD.

neuroscience↗

bioRxiv2025

Neonatal Microglia and Their Secretome as Mediators of Brain Repair

Microglia are essential regulators of myelin integrity and repair, yet their regenerative capacity declines with ageing and in neurodegenerative diseases such as multiple sclerosis (MS). Neonatal microglia retain a uniquely reparative program that may offer insight into restoring lost functions in the adult CNS. Here we show that transplantation of neonatal microglia ameliorates disability, reduces leukocyte infiltration, and promotes remyelination in both inflammatory (EAE) and non-inflammatory (cuprizone) models, and reverses cognitive decline in aged mice. These benefits persisted even when transplanted cells remained confined to the meninges and were reproduced by the neonatal microglia secretome, indicating a paracrine mechanism. Multi-omic profiling revealed that the neonatal secretome is enriched in trophic factors and membrane-building lipids compared to adult microglia, while transcriptomic analyses of treated aged brains showed reactivation of developmental repair pathways and suppression of inflammatory signatures. Together, these results demonstrate that neonatal microglia re-engage rejuvenation-like programs in the adult CNS and highlight the importance of multifactorial strategies, integrating trophic, metabolic, and immunomodulatory cues, over single-target approaches. Our findings establish early microglial programs as a paradigm for designing new regenerative therapies for CNS disorders.

neuroscience↗

bioRxiv2025

A proteogenomic tool uncovers protein markers for human microglial states

Human microglial heterogeneity has been largely described using transcriptomic data. Here, we introduce a microglial proteomic data resource and a Cellular Indexing of Transcriptomes and Epitopes by Sequencing panel enhanced with antibodies targeting 17 microglial cell surface proteins (mCITE-Seq). We evaluated mCITE-Seq on HMC3 microglia-like cells, induced-pluripotent stem cell-derived microglia (iMG), and freshly isolated primary human microglia. We identified novel protein microglial markers such as CD51 and relate expression of 101 cell surface proteins to transcriptional programs. This results in the identification and validation of three protein marker combinations with which to purify microglia enriched with each of 23 transcriptional programs; for example, CD49D, HLA-DR and CD32 enrich for GPNMBhigh ("disease associated") microglia. Further, we identify and validate proteins - SIRPA, PDPN and CD162 - that differentiate microglia from infiltrating macrophages. The mCITE-Seq panel enables the transition from RNA-based classification and facilitates the functional characterization and harmonization of model systems.

neuroscience↗

bioRxiv2025

Age-associated inflammatory monocytes are increased in menopausal females and reversed by Hormone Replacement Therapy

Biological sex is a crucial, but poorly understood variable in age-related susceptibility to infections and chronic inflammation - inflammageing. Monocytes are important immune cells responsible for initiating and resolving inflammatory responses to infection. While changes in monocyte populations result in increased susceptibility to infection, there is limited research on the impact of age and sex on human monocyte phenotype and function. The aim of this work was to dissect the impact of increasing age and biological sex on human monocyte phenotype and function. Here we show that older females have increased inflammatory intermediate and non-classical monocytes compared to young. These monocyte subsets were the most inflammatory ex vivo and their frequency correlated with markers of systemic inflammation. Proteomic analysis of sorted monocyte populations demonstrated that the three human monocyte subsets have largely distinct phenotypes. Additionally, proteomic analysis identified key age-associated protein pathways, including complement cascade and phagocytosis, downregulated in monocytes from older compared to younger individuals. We confirmed the proteomics findings showing that circulating C3 concentrations were reduced with age in females but not males. This decrease in complement in older females resulted in reduced monocyte phagocytosis. Crucially, we demonstrate that in peri/menopausal females, Hormone Replacement Therapy (HRT) reversed this expansion in intermediate monocytes and decreased circulating CRP as compared to age matched controls. Importantly peri/menopausal females on HRT had increased C3 serum concentrations and significantly improved monocyte phagocytosis. The data presented here indicate the importance of menopause in ageing monocyte phenotype and function. This data highlights the potential use of HRT in restoring monocyte function in females during ageing.

immunology↗

bioRxiv2022

Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand1,2. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.

neuroscience↗

bioRxiv2022

Deep proteomic analysis of human microglia and model systems reveal fundamental biological differences of in vitro and ex vivo cells

Using high resolution quantitative mass spectrometry, we have generated the most comprehensive human and mouse microglia proteomic datasets to date, consisting of over 11,000 proteins across all six microglia groups. Microglia from different sources share a core protein signature of over 5600 proteins, yet fundamental differences are observed between species and culture conditions, indicating limitations for human disease modelling in mouse or in in vitro cultures of microglia. Mouse ex vivo microglia show important differences at the proteome level such as differential expression of inflammation and Alzheimers Disease associated proteins. We identify a tenfold difference in the protein content of ex vivo and in vitro cells and significant proteome differences associated with protein synthesis, metabolism, microglia marker expression and environmental sensors. Culturing microglia induces rapidly increased growth, protein content and inflammatory protein expression. These changes can be restored by engrafting in vitro cells into the brain, with xenografted hESC-derived microglia closely resembling microglia from human brain. This data provides an important resource for the field and highlights important considerations needed when using model systems to study human physiology and pathology of microglia.

neuroscience↗