Biology subjects

Whitehead, S. N.

Publications and source records attributed to Whitehead, S. N..

5 recordsLinked to original sources

bioRxiv2025

Microglial morphology reflects cognitive status in the aging rat brain

Age-related cognitive decline affects millions of individuals worldwide, but the cellular mechanisms underlying this decline remain incompletely understood. Microglia undergo significant changes with aging, including alterations in morphology, that may reflect or contribute to cognitive dysfunction. However, the relationship between specific microglial morphologies and cognitive performance in relevant brain regions remains poorly understood. To address this, we evaluated the relationship between morphology-based microglial phenotypes and cognitive performance across domains affected by aging. Microglial morphology was analyzed in four cognitive brain regions of male and female 3-, 9-, and 15-month-old rats and features were subjected to hierarchical clustering on principal components to identify microglial subtypes. Rats underwent cognitive testing using a radial arm water maze and a T-maze set-shifting task to assess spatial working and reference memory, striatal-based learning, and cognitive flexibility. We observed age-related cognitive impairments alongside region-specific changes in microglial morphotype abundance. Importantly, the relative abundance of distinct microglial clusters correlated with cognitive performance in functionally relevant brain regions including the prefrontal cortex, the orbitofrontal cortex, and the hippocampus. Taken together, these findings highlight the utility of morphological profiling in capturing microglial heterogeneity and suggest that morphological changes may reflect or contribute to cognitive decline during aging.

neuroscience↗

bioRxiv2025

Characterizing a hallmark of glymphatic insufficiency: Wasteosomes accumulate in periventricular white matter hyperintensities and exhibit complex relationships with mixed pathology, sclerotic index and perivascular space

The glymphatic system is a recently elucidated waste clearance system in the brain, thought to be critical for the maintenance of homeostasis. Corpora amylacea or "wasteosomes", are discontinuous lipid labyrinth structures that are polyglucosan rich, retain cellular waste and are thought to be of astrocytic origin. Wasteosomes have been proposed as a hallmark of glymphatic insufficiency predominantly due to: 1) their spatial localization around glymphatic drainage points including periventricular (PV) regions, perivascular spaces (PVS), and sub-pial regions; and, 2) their correlation with aging, vascular disorders, neurodegenerative diseases, and conditions that impair sleep. White matter hyperintensities (WMHs) are diffuse hyperintense areas seen on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans that represent damage to white matter. PV WMHs and are known predictors of mild cognitive impairment, stroke, dementia and death. The relationship between wasteosome accumulation, PV WMHs, vascular pathology and PVS is currently unknown. For the first time, in a mixed diagnostic cohort of pathologically diagnosed: Alzheimers disease (AD), cerebrovascular disease (CVD), mixed AD/CVD, and control tissue with no pathological diagnosis, we connected the histopathological wasteosome profile in periventricular brain sections in relation to 7T FLAIR-MRI confirmed PV WMHs, vascular stenosis and PVS. Our results reveal wasteosomes accumulate in PV WMHs, are increased in proximity to large PV venules, and exhibit complex relationships with WMH severity, mixed pathology, sclerotic index and PVS. These findings suggest wasteosomes may serve as histological markers of impaired glymphatic drainage and provide new insights into the pathophysiology underlying white matter injury.

neuroscience↗

bioRxiv2025

Increased circulating TREM2+ microglia extracellular vesicles in aged APP/PS1 Alzheimer's disease rats

INTRODUCTIONTREM2 is a microglial marker important in Alzheimers disease (AD) pathogenesis, but current methods to detect microglial TREM2 expression in vivo are limited. Circulating microglia-derived extracellular vesicles (EVs) show promise as potential biomarkers for AD and may offer insight into TREM2 activity. METHODSTMEM119+/TREM2+ EVs were assessed using nanoscale flow cytometry in plasma from wildtype and APP/PS1 rats aged to 3-, 9-, and 15-months-old. Molecular and histological assays were used to assess microglia markers in rat brain tissue and a radial arm water maze task was employed to evaluate spatial working and reference memory. RESULTSCirculating TMEM119+/TREM2+ EVs were increased in 15-month APP/PS1 rats and associated with severity of cognitive impairment. TREM2 brain expression varied by anatomical region, age, transgene, and assay. DISCUSSIONCollectively, this study provides the first assessment of TMEM119+/TREM2+ EVs as a biomarker of brain microglial expression and cognition in an AD rat model.

neuroscience↗

bioRxiv2025

Lipidomic signatures in microglial extracellular vesicles during acute inflammation: a gateway to neurological biomarkers

Extracellular vesicles (EVs) are membrane bound vesicles released from all cells throughout the body, including the central nervous system, and are known to carry both membrane-bound proteins and cargo reflective of their cell of origin. EVs show promise as neurological disease biomarkers due to their molecular makeup reflecting their parent-cell composition signature and due to their ability to cross the blood-brain barrier. To-date, the vast majority of research in this field has explored the protein profiles of EVs; however, lipids play an important role not only in the formation of EVs, but also in mediating cellular function and the pathological progression of many neurodegenerative conditions. Herein, we take a critical first step in determining the potential utility of EV lipids as biomarkers in neurological disease. In vitro we exposed BV-2 microglia to either control media or media containing lipopolysaccharides (LPS), a known pro-inflammatory stimulus, for 24 hours then isolated both the cells and their EVs and performed LC-MS/MS. For the first time, we reveal distinct lipidomic changes can differentiate resting vs. pro-inflammatory microglia and their EVs, while distinct lipids are preserved between EVs and their parent cell. Moreover, we add to current literature by demonstrating acute pro-inflammatory activation of microglia results in the activation and suppression of distinct lipidomic pathways. Finally, we demonstrate that analysis of lipid-based relationships between parent cells and their EVs may be a useful tool to infer cellular function. This study is the first of its kind to demonstrate that lipidomic analysis can not only differentiate the functional state of cells in vitro but can also differentiate their EVs. We lay the first brick in a foundation to support future research into EV lipids as novel and exciting biomarker candidates in neurological disease.

neuroscience↗

bioRxiv2024

White matter microglia morphological changes with aging in guinea pig offspring born growth restricted

Fetal growth restriction is implicated in the programming of later-life neurodegeneration. We hypothesized that growth restricted offspring would show accelerated changes to microglial white matter morphology, relative to controls. Control guinea pig sows were fed ad libitum, while maternal nutrient restriction sows received 70% of control diet switched to 90% from mid-gestation. Offspring were sacrificed at [~]26 days (neonate) or [~]110 days (adult) postpartum. Coronal brain sections from the frontal cortex were subject to IBA1-staining for microglial detection and analyzed by machine learning software. At birth, total body weight of growth restricted offspring was reduced relative to control (p<0.0001) with postnatal catch-up growth observed. Microglial density was reduced in the corpus callosum of control (p<0.05) and growth restricted (p=0.13) adults, relative to neonates. Adults from both groups showed greater IBA1-positive area in the cingulum and periventricular white matter (p<0.05) and increased microglial fractal dimension in the corpus callosum (p<0.10) and periventricular white matter (p<0.05), relative to neonates. At the timepoints studied, we report age-related changes in white matter microglial morphology. However, maternal nutrient restriction leading to fetal growth restriction in guinea pigs does not appear to exacerbate these white matter microglia morphological changes as a marker for later-life neurodegeneration.

developmental biology↗