Biology subjects

Mack, W. J.

Publications and source records attributed to Mack, W. J..

9 recordsLinked to original sources

bioRxiv2026

Single cell profiling reveals GSM-15606 attenuates air pollution-induced inflammation and preserves hippocampal neurogenesis

1.IntroductionAir pollution (AirPoll) is a major environmental risk factor for age-related cognitive decline and dementia, yet we poorly understood the cellular and molecular mechanisms underlying its effects and their potential attenuation. MethodsWe combined single cell RNA sequencing with immunohistochemistry to determine transcriptional responses in microglia, astrocytes, neurons and neural stem cells in the hippocampus of mice following exposure to chronic diesel exhaust particle (DEP). Differential gene expression profiles were compared between filtered-air and DEP exposed animals. The gamma secretase modulator GSM-15606 (BPN) was used to probe selective rescue of inflammatory signatures across distinct cell populations. ResultsDEP exposure triggered robust inflammatory programs in microglia and astrocytes, including upregulation of cytokine signaling components, innate immune receptors, stress-responsive transcription factors, and markers of reactive glial phenotypes. In neural stem cells, DEP induced activation of gliosis-associated pathways, including Il6st, Stat3, and Txnip, consistent with a pro-inflammatory state that may bias lineage decisions. Immunostaining confirmed a significant reduction in immature neurons in the neurogenic niche after AirPoll exposure. GSM-15606 attenuated many DEP-induced transcriptional alterations in microglia and astrocytes, reducing expression of inflammatory mediators and reactive gliosis markers, but did not modulate the inflammatory profile of neural stem cells. ConclusionsAirPoll activates divergent inflammatory pathways across hippocampal cell populations and suppresses neurogenesis. Targeting inflammation with GSM-15606 selectively reverses glial but not neural stem cell responses, highlighting cell-type-specific mechanisms and potential therapeutic pathways to mitigate pollution-related cognitive vulnerability. These results support GSM-15606 as a protective agent against AirPoll-induced hippocampal dysfunction and amyloidogenic stress.

neuroscience↗

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

Exploring the association between walking, sleep patterns, brain perivascular spaces, and cognitive function in Parkinson's disease

Perivascular spaces (PVSs) support brain waste clearance and are influenced by sleep. In Parkinsons disease (PD), sleep is often disrupted, and can co-occur with gait dysfunction. This study investigated how sleep disruption, walking difficulties, and cognition relate in PD, considering PVS as a mediator. Our cohort included 348 participants -healthy controls (HC, n=59), prodromal (n=117), and PD patients (n=172)-in the Parkinsons Progression Markers Initiative (PPMI) study. Insomnia and walking issues were assessed by questionnaire, cognition was measured with the Symbol Digit Modalities (SDM) test, and PVS volume fraction in white matter (WM-PVS) and basal ganglia (BG-PVS) was quantified. PVS did not mediate the relationship between sleep or motor problems, on cognition. Walking difficulties were directly linked to poorer cognition, and insomnia to walking deficits. BG-PVS was negatively associated with cognition. PVS burden predicted cognitive function after five years, but not disease progression as indexed by cerebro-spinal fluid (CSF) biomarkers. These findings suggest walking deficits directly relate with cognition in PD, but the relationship is not mediated by PVS.

neuroscience↗

bioRxiv2025

Perivascular space mediated the interaction between sleep, and brain functional connectivity in the healthy aging population

Perivascular space (PVS) surrounds the perforating arteries or draining veins of the cerebral cortex as part of the brain clearance system. Previous studies showed that sleep aTects both brain clearance function and brain functional connectivity (FC). However, the impact of PVS characteristics on brain FC remains unclear. This study investigated these associations and their link to cognition. We utilized cross-sectional structural MRI and resting state-fMRI data from 512 health aging population in the HCP-Aging dataset, together with Pittsburgh Sleep Quality Index questionnaire and NIH cognitive tests. Our results showed that basal ganglia (BG)-PVS volume fraction (VF) was positively correlated with FC in the right anterior medial temporal gyrus (aMTG) and right temporal regions, while centrum-semiovale (CSO)-PVS VF was positively correlated with FC in the left hippocampus and right frontal regions. Increased CSO-PVS VF in early middle-aged adults showed higher hippocampal FC and better cognitive performance. Interestingly, individuals with longer time spent in bed had larger BG-PVS VF linked to higher FC in the right aMTG. Additionally, older adults with better sleep quality had larger BG-PVS VF linked to higher FC in the right aMTG. These findings suggest that PVS morphology may reflect changes in neural connections involved in memory-related regions.

neuroscience↗

bioRxiv2025

Down syndrome with Alzheimers disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis

INTRODUCTIONCerebral microbleeds (MB) are associated with sporadic Alzheimers Disease (AD) and Down Syndrome with AD (DSAD). Higher MB iron may cause iron mediated lipid peroxidation. We hypothesize that amyloid deposition is linked to MB iron and that amyloid precursor protein (APP) triplication increases iron load and lipid peroxidation. METHODSPrefrontal cortex and cerebellum of cognitively normal (CTL), AD and DSAD ApoE3,3 carriers were examined for proteins that mediated iron metabolism, antioxidant response, and amyloid processing in lipid rafts. RESULTSIron was 2-fold higher in DSAD than CTL and AD. Iron storage proteins and lipid peroxidation were increased in prefrontal cortex, but not in the cerebellum. The glutathione synthesis protein GCLM was decreased by 50% in both AD and DSAD. Activity of lipid raft GPx4, responsible for membrane repair, was decreased by at least 30% in AD and DSAD. DISCUSSIONDSAD shows greater lipid peroxidation than AD consistent with greater MBs and iron load. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/636731v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@fd0d2aorg.highwire.dtl.DTLVardef@16b65d5org.highwire.dtl.DTLVardef@1eab2ddorg.highwire.dtl.DTLVardef@184e6d2_HPS_FORMAT_FIGEXP M_FIG C_FIG Cerebral microbleeds result in increased brain iron and lipid peroxidation in DSAD consistent with ferroptosis as reported for Alzheimers disease. A{beta}; beta-amyloid peptides, APP; amyloid precursor protein, GCLC; glutathione cysteine ligase catalytic subunit, GCLM; glutathione cysteine modifier subunit, GPx4; glutathione peroxidase 4, HNE; 4-hydroxynonenal. RESEARCH IN CONTEXTO_LISystematic Review: DS is associated with increased microbleeds and brain iron that may be mediated by increased APP from Trisomy 21. To assess potential links between amyloid and iron levels, we examined sporadic and DS with AD brains for amyloid processing and antioxidant enzyme defense in lipid rafts. We further compared DSAD with rare variants of DS: partial and mosaic T21. C_LIO_LIInterpretation: DSAD brains showed greater oxidation of lipid rafts where APP is processed than sporadic AD. Corresponding decreases in lipid raft antioxidant enzymes, despite increased total levels of these antioxidant enzymes, present a new mechanism for aberrant amyloid processing during AD. C_LIO_LIFuture Directions: Iron chelation therapies in combination with amyloid monoclonals may benefit DSAD. C_LI

neuroscience↗

bioRxiv2024

Increased cerebrospinal fluid and plasma apoE glycosylation is associated with reduced levels of Alzheimer's disease biomarkers

The apolipoprotein E (APOE) {varepsilon}4 allele is the strongest genetic risk factor for Alzheimers disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites, yet the impact and function of this glycosylation on AD biomarkers remains unclear. We examined apoE glycosylation in a cohort of cerebrospinal fluid (CSF, n=181) and plasma (n= 178) samples from the Alzheimers Disease Neuroimaging Initiative (ADNI) stratified into 4 groups: cognitively normal (CN), Mild Cognitive Impairment (MCI), progressors and non-progressors based on delayed word recall performance over 4 years. We observed decreasing glycosylation from apoE2 > apoE3 > apoE4 in CSF, and in plasma (apoE3 > apoE4). ApoE glycosylation was reduced in the MCI compared with CN groups, and in progressors compared to non-progressors. In CSF, higher apoE glycosylation associated cross-sectionally with lower total tau (t-tau), p-tau181, and with higher A{beta}1-42. Similar associations of apoE glycosylation with higher A{beta}1-42 were observed in plasma. In CSF, greater apoE4 glycosylation was associated with lower t-tau and p-tau181. Over a 6-year period, higher baseline levels of CSF apoE glycosylation predicted lower rates of increase in CSF t-tau and p-tau181 and lower rates of decrease in CSF A{beta}1-42. These results indicate strong associations of apoE glycosylation with biomarkers of AD pathology independent of apoE genotype, warranting a deeper understanding of the functional role of apoE glycosylation on AD tau pathology.

neuroscience↗

bioRxiv2023

Perivascular spaces in Alzheimer's disease are associated with inflammatory, stress-related, and hypertension biomarkers

Perivascular spaces (PVS) are fluid-filled spaces surrounding the brain vasculature. Literature suggests that PVS may play a significant role in aging and neurological disorders, including Alzheimers disease (AD). Cortisol, a stress hormone, has been implicated in the development and progression of AD. Hypertension, a common condition in older adults, has been found to be a risk factor for AD. Hypertension may contribute to PVS enlargement, impairing the clearance of waste products from the brain and promoting neuroinflammation. This study aims to understand the potential interactions between PVS, cortisol, hypertension, and inflammation in the context of cognitive impairment. Using MRI scans acquired at 1.5T, PVS were quantified in a cohort of 465 individuals with cognitive impairment. PVS was calculated in the basal ganglia and centrum semiovale using an automated segmentation approach. Levels of cortisol and angiotensin-converting enzyme (ACE) (an indicator of hypertension) were measured from plasma. Inflammatory biomarkers, such as cytokines and matrix metalloproteinases, were analyzed using advanced laboratory techniques. Main effect and interaction analyses were performed to examine the associations between PVS severity, cortisol levels, hypertension, and inflammatory biomarkers. In the centrum semiovale, higher levels of inflammation reduced cortisol associations with PVS volume fraction. For ACE, an inverse association with PVS was seen only when interacting with TNFr2 (a transmembrane receptor of TNF). There was also a significant inverse main effect of TNFr2. In the PVS basal ganglia, a significant positive association was found with TRAIL (a TNF receptor inducing apoptosis). These findings show for the first time the intricate relationships between PVS structure and the levels of stress-related, hypertension, and inflammatory biomarkers. This research could potentially guide future studies regarding the underlying mechanisms of AD pathogenesis and the potential development of novel therapeutic strategies targeting these inflammation factors.

neuroscience↗

bioRxiv2020

Combined protein and transcript single cell RNA sequencing reveals cardiovascular disease and HIV signatures

Cryopreserved peripheral blood mononuclear cells (PBMCs) are frequently collected and provide disease- and treatment-relevant data in clinical studies. Here, we developed combined protein (40 antibodies) and transcript single cell (sc)RNA sequencing in PBMCs. Among 31 participants in the WIHS Study, we sequenced 41,611 cells. Using Boolean gating followed by Seurat UMAPs and Louvain clustering, we identified 58 subsets among CD4 T, CD8 T, B, NK cells and monocytes. This resolution was superior to flow cytometry, mass cytometry or scRNA-sequencing without antibodies. Since the transcriptome was not needed for cell identification, combined protein and transcript scRNA-Seq allowed for the assessment of disease-related changes in transcriptomes and cell type proportion. As a proof-of-concept, we showed such differences between healthy and matched individuals living with HIV with and without cardiovascular disease. In conclusion, combined protein and transcript scRNA sequencing is a suitable and powerful method for clinical investigations using PBMCs.

immunology↗

bioRxiv2020

Alteration of perivascular spaces in early cognitive decline

Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular space. Using magnetic resonance imaging, we show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered perivascular space presence and distribution, irrespective of Amyloid-{beta}. Surprisingly, we noted decreased perivascular space presence in the anterosuperior medial temporal lobe, which was associated with neurofibrillary tau tangle deposition in the entorhinal cortex, one of the hallmarks of early Alzheimers disease pathology. Our results suggest that anatomically-specific alteration of the perivascular spaces may provide an early biomarker of cognitive impairment in aging adults.

neuroscience↗