Biology subjects

DeLuca, G. C.

Publications and source records attributed to DeLuca, G. C..

4 recordsLinked to original sources

bioRxiv2025

The unexpected dual role of S100A9 amyloid protein on neurodegeneration in progressive multiple sclerosis motor cortex

Motor cortical inflammation and neurodegeneration are key features of progressive multiple sclerosis (MS), contributing to irreversible motor disability. However, the precise mechanisms leading to neuronal loss remain poorly understood. While chronic inflammation is a hallmark of MS and contributes to disease progression, the factors linking inflammation to neuronal loss in the cortex are not well defined. One candidate is the calcium-binding protein S100A9, a damage-associated molecular pattern (DAMP) protein, thought to be released by stressed cells and infiltrating monocytes. Through its ability to modulate immune responses and influence neuronal survival, S100A9 may sustain chronic inflammation and participate in neurodegenerative processes. Although its role has been explored in other neurological disorders, its contribution to progressive MS remains largely uncharacterised. Here, we investigated S100A9 expression in the motor cortex of a large post-mortem cohort of MS cases (n=67) and controls (n=9), focusing on its cellular localisation and its relationship with neuronal density and vascular pathology. S100A9 expression was increased in progressive MS cases compared to controls, predominantly localised to intravascular monocytes and as amyloid-like extracellular plaques surrounding blood vessels. These patterns were associated with neurodegeneration and blood-brain barrier (BBB) disruption, as evidenced by correlations with reduced brain weight, decreased neuronal density, and increased fibrin(ogen) deposition. In contrast, S100A9 was also expressed in microglia, where it correlated with increased neuronal density and reduced fibrin(ogen) deposition. Notably, the phosphorylated form of S100A9, linked to pro-inflammatory signaling, was reduced in microglia but enriched in perivascular regions. These findings reveal a dual, compartment-specific role for S100A9 in progressive MS, whereby extracellular aggregates may drive neurotoxicity, while microglial S100A9 may confer neuroprotection. Therapeutic strategies targeting extracellular S100A9 while preserving its intracellular functions may offer new opportunities for treating progressive MS.

neuroscience↗

bioRxiv2024

Aberrant iron deposition in the multiple sclerosis spinal cord relates to neurodegeneration

BackgroundIron accumulates in microglia-macrophages at the edge of multiple sclerosis (MS) lesions in the brain. Iron-rimmed brain lesions strongly predict disability accumulation, supporting iron metabolism is crucial in MS pathology. Little is known about iron distribution in the spinal cord. MethodsAutopsy cervical, thoracic and lumbar spinal cord samples from 9 controls and 46 MS donors of whom a subset (n=36) had mesiofrontal motor cortical tissue available for study, were labelled and systematically assessed for iron (DAB-enhanced Turnbull), myelin (PLP), axons (Palmgren silver), microglia-macrophages (TMEM119, Iba1, CD68), astroglia (GFAP), oligodendroglia (OLIG2), acute axonal injury (B-APP, SMI-32, NPY-1R) and oxidative stress (E06). MS lesional and non-lesional areas were considered. Total non-haem iron was quantified by inductively coupled plasma optical emission spectroscopy (ICP-OES). ResultsIn controls, iron predominantly localised to oligodendrocytes with total non-haem iron relating to total myelin fraction, which markedly differed in MS where iron accumulated in microglia-macrophages, subpial astrocytes, and axons in non-lesional areas. Iron laden microglia-macrophages were over-represented relative to total microglial-macrophages and displayed dysmorphic features. Iron-positive axons showed a disto-proximal gradient (highest at lumbar level) with a predilection for the corticospinal tracts. The extent of iron axon positivity related to smaller spinal cord area, lower total axonal counts, and greater oxidative stress. Iron positivity in each cellular compartment (i.e. subpial astrocytes, microglia-macrophage and axons) related to one-another and total non-haem iron correlated with axonal counts in MS. No iron-rimmed lesions were detected in the spinal cord unlike in cortical grey and subcortical white matter of the same cases where 22% and 80% of iron-rimmed lesions, respectively, were seen. ConclusionsDespite the conspicuous absence of iron-rimmed lesions in the MS spinal cord, we demonstrate widespread aberrant iron distribution in the MS spinal cord that relates to oxidative stress and neurodegeneration independent of demyelination. The distal cord predominant and corticospinal tract specific accumulation of iron in axons mirrors the pattern of length-dependent motoric disability commonly encountered in progressive MS. These findings implicate aberrant iron accumulation as a novel, clinically relevant, feature of MS spinal cord pathology.

neuroscience↗

bioRxiv2024

Neuropathological evidence of reduced amyloid beta and neurofibrillary tangles in multiple sclerosis cortex

Multiple sclerosis (MS) and Alzheimers disease (AD) are neurodegenerative diseases demonstrating age-related accumulation of disability. Inflammation lasting decades is a paradigmatic feature of MS pathology that variably relates to neurodegeneration, while the accumulation of A{beta} plaques and neurofibrillary tangles (NFT) are cornerstones of AD pathology. However, few studies investigated the accumulation of amyloids in MS. We investigated A{beta} deposition and NFT density in temporal or frontal cortices derived from a large post-mortem cohort of MS (n=78) and age and sex-matched control (n=65) cases. We found reduced A{beta} burden in MS cases compared with controls, particularly in cases below 65-years-of-age. NFT were similarly reduced in MS compared to controls, notably in cases above 65 years-of-age. Higher A{beta} deposition predicted greater NFT density in MS. These findings suggest that MS-related factors may influence A{beta} and NFT deposition and/or clearance. This work highlights new therapeutic perspectives relevant for both MS and AD.

pathology↗

bioRxiv2022

Microglia associations with brain pericytes and the vasculature are reduced in Alzheimer's disease

Cerebral blood flow is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimers disease (AD). Subpopulations of microglia have well-characterised associations with the vasculature in the central nervous system but the precise relationship between microglia and cells which exist on the vasculature is not yet clear. In this study we explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the regulation of cerebral blood flow and maintenance of the blood brain barrier. Using fixed tissue sections and in vivo live imaging, we discovered a subset of microglia that closely associated with pericytes, termed PEricyte-associated Microglia (PEM). PEM are present throughout all regions of the brain and spinal cord in NG2DsRed x CX3CR1+/GFP mice, and in the human frontal cortex. They reside adjacent to pericytes at all levels of the capillary tree and can maintain their position for at least 28 days. PEM associate with pericytes lacking astroglial endfeet coverage but are segregated from pericytes by capillary basement membranes and capillary vessel width is similarly increased beneath pericytes with or without an associated PEM. Deletion of the microglia fractalkine receptor (CX3CR1) did not disrupt the association between pericytes and PEM, suggesting the association is not reliant on fractalkine signalling. Finally, we found that the proportion of microglia that are capillary-associated and PEM declines in the superior frontal gyrus (SFG) in AD, which is exacerbated by the APOE {varepsilon}3/{varepsilon}4 genotype. In summary, we identify and characterise a subpopulation of microglia that specifically associate with pericytes and find this population is reduced in the SFG in AD. This reduction may be a novel mechanism contributing to vascular dysfunction in diseases such as AD.

neuroscience↗