Biology subjects

Demetriou, A.

Publications and source records attributed to Demetriou, A..

4 recordsLinked to original sources

bioRxiv2026

Induction of ferroptotic and amyloidogenic signatures linked to Alzheimers disease by chemically distinct air pollutants

Air pollution (AirP) exposure is associated with increased Alzheimers disease (AD) risk, yet AirP is chemically heterogeneous, complicating identification of shared pathogenic drivers. We examined acute cortical responses to two metal-rich AirP sources, diesel exhaust particles (DEP) and World Trade Center (WTC) dust, and compared them to woodsmoke (WS), a particulate exposure with low metal content. DEP and WTC elicited highly convergent transcriptional responses, sharing over 1200 differentially expressed genes linked to inflammation, ferroptosis, neuronal remodeling, and amyloid processing. These changes were accompanied by impaired antioxidant activity and increased lipid peroxidation within lipid rafts, a membrane microdomain critical for amyloid processing, resulting in increased A{beta} generation. In contrast, WS produced a distinct transcriptional signature and failed to induce ferroptotic priming or lipid peroxidation, consistent with its low metal composition. Together, these findings implicate metals as a shared driver linking diverse AirP exposures to amyloidogenic vulnerability and elevated AD risk. Graphical AbstractAcute AirP exposure converges on ferroptotic priming, amyloidogenic processing, and white-matter vulnerability. Acute exposure to metal-rich AirP, such as DEP or WTC introduces redox-active metals and particulate matter that promote lipid peroxidation, amyloidogenesis, and altered transcriptional regulation in the brain. AirP exposure engages xenobiotic metabolism pathways (AhR/ARNT), activates iron and heme handling through ferritinophagy (NCOA4) and heme oxygenase activity (HMOX1), and blunts lipid peroxide detoxification systems, including glutathione peroxidase 4 (GPx4), ferroptosis suppressor protein 1 (FSP1), and glutathione (GSH) synthesis. These changes promote ferroptotic priming and lipid raft oxidation, facilitating amyloid precursor protein (APP) processing by secretases (ADAM10, BACE1, {gamma}-secretase) and increasing amyloid-{beta} (A{beta}) generation. In parallel, transcriptional and cell-state remodeling involving neuronal and oligodendrocyte responses contribute to selective white-matter vulnerability, particularly within the corpus callosum. Together, these pathways provide a mechanistic framework linking acute AirP exposure to convergent oxidative, amyloidogenic, and microstructural changes relevant to Alzheimers disease pathology. O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/696601v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@3a22dcorg.highwire.dtl.DTLVardef@c6ae26org.highwire.dtl.DTLVardef@1d3412forg.highwire.dtl.DTLVardef@5cb011_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Alzheimer's Disease Mutations Disrupt Neural Stem Cell Fate and Early Brain Development

Alzheimers disease (AD) has been largely considered as an age-related disease, mainly affecting mature or aging adult brain. Recent studies show that AD-associated mutations could impair early life, even during neurodevelopment. However, due to the complex of AD mutations and neurodevelopmental regulations, how mutations in specific genes affect the origin of neurodevelopment is still largely under studied. In this study, we investigate how AD mutations in App gene impact neurodevelopment, with a focus on NSC dynamics and the balance between neurogenesis and gliogenesis. We employed the 5xFAD transgenic line and the APPNL-G-F knock-in model, RNA sequencing, neurosphere assay and histological analyses on the cortex and hippocampus across critical developmental timepoints. Our results reveal that the APPNL-G-F model exhibits early gene expression changes, with suppressed stem cell proliferation, impaired neurogenesis, upregulation of gliogenesis and enhanced neuroinflammatory pathways. In contrast, the 5xFAD model displays minimal embryonic differences, with pronounced postnatal alterations likely driven by both gene mutations and APP overexpression. These findings indicate that AD mutations can inherently impair NSC self-renewal and differentiation, resulting in a suboptimal brain structure that have potentially higher vulnerability towards AD pathology in later life.

developmental biology↗

bioRxiv2024

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer

BackgroundBacillus Calmette-Guerin (BCG) is the standard of care treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), yet many patients develop recurrent disease despite evidence of ongoing immune activation. We investigated mechanisms of immune escape in BCG-unresponsive tumors and evaluated the therapeutic potential of targeting the HLA-E/NKG2A axis. MethodsSingle-cell RNA sequencing, spatial immunophenotyping, proteomic profiling, and functional ex vivo assays were performed using tumors and urine samples from patients with BCG-naive and BCG-unresponsive NMIBC. ResultsBCG-unresponsive tumors were enriched for HLA-E-expressing malignant cells compared with BCG-naive tumors. Increased HLA-E expression was associated with enhanced IFN-{gamma} signaling and was induced by IFN-{gamma} stimulation in primary tumor cells and bladder cancer tumor lines. Spatial analyses demonstrated accumulation of NKG2A+ NK and CD8 T cells in proximity to HLA-Ehigh tumor cells, with increased NKG2A:HLA-E interactions in BCG-unresponsive tumors. Despite high expression of cytotoxic mediators, NKG2A+ effector cells displayed impaired degranulation. Blockade of NKG2A with monalizumab restored degranulation of and cytotoxicity by tumor-infiltrating lymphocytes in autologous tumor co-cultures. ConclusionsBCG-unresponsive NMIBC tumors are enriched for HLA-E-expressing tumor cells and NKG2A+ effector lymphocytes, with increased engagement of the HLA-E/NKG2A axis within the tumor microenvironment. These findings identify the HLA-E/NKG2A axis as a therapeutic vulnerability and provide a rationale for clinical evaluation of NKG2A blockade as a bladder-sparing strategy for patients with BCG-unresponsive disease.

cancer biology↗

bioRxiv2024

ERβ mediates sex-specific protection in the App-NL-G-F mouse model of Alzheimer's disease

Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimers disease (AD). Activation of estrogen receptor beta (ER{beta}) can be clinically relevant since it avoids the negative systemic effects of ER activation. However, very few studies have explored ER{beta}-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ER{beta} in mediating sex-specific protection against AD pathology in the clinically relevant AppNL-G-F knock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and female AppNL-G-F mice with the selective ER{beta} agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ER{beta}-knockout mice were used to assess ER{beta}s effect on microglial activation and phagocytosis. We find that ER{beta} activation protects against amyloid pathology and cognitive decline in male and female AppNL-G-F mice. Ovariectomy increased soluble amyloid beta (A{beta}) in cortex and insoluble A{beta} in hippocampus, but had otherwise limited effects on pathology. We further identify that ER{beta} does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ER{beta} protects against AD pathology differently in males and females, warranting reassessment of ER{beta} in combating AD.

neuroscience↗