Biology subjects

Harms, A. S.

Publications and source records attributed to Harms, A. S..

9 recordsLinked to original sources

bioRxiv2026

Stage-Specific NF-κB RelA and IRF4 Programs Drive -Synuclein-Induced Disease-Associated Microglia Differentiation

Microglial activation in response to aggregated -synuclein (-syn) accumulation is a pathological hallmark of Parkinson disease (PD). A distinct activated microglial state, disease-associated microglia (DAM), has been identified across multiple neurodegenerative disorders, including PD. However, the transcriptional and epigenetic programs governing DAM differentiation remain unclear. Here, we show that neuronal -syn overexpression drives progressive microglial state transitions toward DAM, accompanied by increased phagocytic activity and enhanced cytokine and chemokine production. Integrative transcriptomic and chromatin accessibility analyses reveal a hierarchical NF-{kappa}B--AP-1--IRF regulatory program underlying these state transitions. Microglial NF-{kappa}B p65 (RelA) or IRF4 deficiency impairs microglial progression toward DAM, with RelA and IRF4 governing early microglial activation and subsequent DAM differentiation, respectively. Enrichment of NF-{kappa}B, AP-1, and IRF motifs in DAM in human PD supports conservation of this regulatory program across species. Together, our findings establish RelA and IRF4 as sequential, stage-specific regulators that coordinate -syn-induced DAM differentiation in PD.

immunology↗

bioRxiv2025

High-Dimensional Single-Cell Analysis Reveals Coordinated Age-Dependent Neuroinflammatory Microglia-T cell Circuits in the Brain

Aging and cerebrovascular pathology drive neuroinflammation in vascular dementia (VaD) but immune mechanisms underlying this interplay remain unresolved. Leveraging multi-modal high-dimensional imaging, flow cytometry, and split pool ligation transcriptomic sequencing in a mouse model of VaD, we constructed a brain immune cell atlas spanning young and aged mice in health and disease. We profiled microglia, T cells, macrophages, neutrophils, and B cells and integrated transcriptomics, cell-cell communication, multiplex imaging, and comparative analysis with human microglia. We found striking depletion of Ccr7+ naive T cells and expansion of Gzmk+ cytotoxic Cd8+ effector memory T cells in the aging brain. At the same time, microglia shifted toward a pro-inflammatory state with enhanced activity of major histocompatibility class complex I (MHC-I) to T cell receptor and co-stimulation from CD86 to CD28. These shifts suggest enhanced neuroinflammatory polarization within the aged brain and in VaD. These signals were strongest from activated microglia to Gzmk+ Cd8+ TEM cells, indicating that age-related microglial polarization may sustain cytotoxic T cell activation in the aged brain. Our findings suggest pro-inflammatory microglia and Gzmk+ CD8+ TEM cells are central drivers of immune brain aging and highlights a therapeutic potential to disrupt age-related neuroinflammatory cascades in VaD.

immunology↗

bioRxiv2024

Amyloid-beta, alpha-synuclein and tau aggregated co-pathologies enhance neuropathology and neuroinflammation

Alzheimers (AD) and Parkinson disease (PD) pathology often co-occur. Amyloid-{beta} and phosphorylated tau are found in 30-50% of idiopathic PD cases, while -synuclein inclusions are present in 50% of AD cases. These co-pathologies are linked to increased mortality and earlier onset of cognitive decline. Immune activation is a hallmark of these neurodegenerative diseases, but current models primarily examine each pathology in isolation. How these co-pathologies drive inflammation and neuronal loss remains poorly understood. We therefore developed a mouse model combining tau, amyloid-{beta}, and -synuclein. We found that co-pathologies synergistically trigger an amplified neuroimmune response, with expanded populations of CD4+ and CD8+ tissue-resident memory T cells and CD68+ microglia, compared to single pathologies. These changes were abundant in the hippocampus and cortex, regions with elevated protein pathology load and enhanced neuronal loss. Our findings demonstrate that co-pathologies enhance proteinopathy and synergistically enhance immune activation and neurodegeneration, suggesting that combinatorial therapeutic strategies that target both co-pathologies and inflammation, may be disease modifying. SummaryWebster et al. demonstrate that co-occurring Alzheimers and Parkinson disease protein pathologies, common in cognitively impaired patient populations, amplify proteinopathy and synergistically enhance CNS neuroinflammatory responses and neurodegeneration. This work supports the need for combinatorial therapeutic strategies and positions neuroinflammation as an important link for co-pathology enhanced neurodegeneration.

neuroscience↗

bioRxiv2024

Tissue resident memory CD8+ T cells are present but not critical for demyelination and neurodegeneration in a mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is rare, fast progressing, and fatal synucleinopathy with alpha-synuclein (-syn) inclusions located within oligodendroglia called glial cytoplasmic inclusions (GCI). Along with GCI pathology there is severe demyelination, neurodegeneration, and neuroinflammation. In post-mortem tissue, there is significant infiltration of CD8+ T cells into the brain parenchyma, however their role in disease progression is unknown. To determine the role of CD8+ T cells, a modified AAV, Olig001-SYN, was used to selectively overexpress -syn in oligodendrocytes modeling MSA in mice. Four weeks post transduction, we observed significant CD8+ T cell infiltration into the striatum of Olig001-SYN transduced mice recapitulating the CD8+ T cell infiltration observed in post-mortem tissue. To understand the role of CD8+ T cells, a CD8 knockout mice were transduced with Olig001-SYN. Six months post transduction into a mouse lacking CD8+ T cells, demyelination and neurodegeneration were unchanged. Four weeks post transduction, neuroinflammation and demyelination were enhanced in CD8 knockout mice compared to wild type controls. Applying unbiased spectral flow cytometry, CD103+, CD69+, CD44+, CXCR6+, CD8+ T cells were identified when -syn was present in oligodendrocytes, suggesting the presence of tissue resident memory CD8+ T (Trm) cells during MSA disease progression. This study indicates that CD8+ T cells are not critical in driving MSA pathology but are needed to modulate the neuroinflammation and demyelination response.

neuroscience↗

bioRxiv2024

Alpha-synuclein overexpression can drive microbiome dysbiosis in mice

Growing evidence indicates that persons living with Parkinson disease (PD), have a unique composition of indigenous gut microbes. Given the long prodromal or pre-diagnosed period, longitudinal studies of the human and rodent gut microbiome prior to symptomatic onset and for the duration of the disease period are currently lacking. PD is characterized in part by accumulation of the protein -synuclein (-syn) into insoluble aggregates, in both the central and enteric nervous systems. As such, a number of experimental rodent and non-human primate models of -syn overexpression recapitulate some of hallmark pathophysiologies of PD. These animal models provide an opportunity to assess how the gut microbiome changes with age under disease relevant conditions. Here, we used a transgenic mouse strain, the Thy1-hSYN "line 61" mice which over express wild-type human -syn to test how the gut microbiome composition responds in this model of PD pathology during aging. Using shotgun metagenomics, we find significant, age and genotype dependent bacterial taxa that become altered over age. We reveal that -syn overexpression can drive alterations to the gut microbiome composition and suggest that it limits the expansion of diversity through age. Given emerging data on potential contributions of the gut microbiome to PD pathologies, our data provide an experimental foundation to understand how the PD-associated microbiome may arise as a trigger or co-pathology to disease.

microbiology↗

bioRxiv2022

IFNγ drives neuroinflammation and demyelination in a mouse model of multiple system atrophy

Multiple system atrophy (MSA) is a rare and fatal synucleinopathy characterized by insoluble alpha-synuclein (-syn) cytoplasmic inclusions located within oligodendroglia. Neuroinflammation, demyelination, and neurodegeneration are correlated with areas of GCI pathology, however it is not known what specifically drives disease pathogenesis. Recently in a mouse model of MSA, CD4+ T cells have been shown to drive neuroinflammation and demyelination, however the mechanism by which this occurs also remains unclear. In this study we use genetic and pharmacological approaches in a novel model of MSA to show that the pro-inflammatory cytokine interferon gamma (IFN{gamma}) drives neuroinflammation and demyelination. Furthermore, using an IFN{gamma} reporter mouse, we found that infiltrating CD4+ T cells were the primary producers of IFN{gamma} in response to -syn overexpression in oligodendrocytes. Results from these studies indicate that IFN{gamma} expression in CD4 T cells drives -syn-mediated neuroinflammation and demyelination, and strategies to target IFN{gamma} expression may be a potential disease modifying therapeutic strategy for MSA.

neuroscience↗

bioRxiv2022

Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease

Dopaminergic cell loss due to the accumulation of -syn is a core feature of PD pathogenesis. Neuroinflammation specifically induced by -syn has been shown to exacerbate neurodegeneration, yet the role of CNS resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating -syn related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response. Surprisingly, the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, -syn expression led to an expansion in BAM numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that BAMs played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, BAMs were identified in post-mortem PD brain in close proximity to T cells. These results point to a critical role for BAMs in mediating PD pathogenesis through their essential role in the orchestration of the -syn-mediated neuroinflammatory response.

neuroscience↗

bioRxiv2022

Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson ' Disease

While Parkinsons disease (PD) remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that PD consists of multiple pathologies, but it is unclear which occurs first and which are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits (MMD). Motor deficits were determined on a modified and validated Unified Parkinsons Disease Rating Scale III (UPDRS III), but they occur to a degree insufficient to diagnose PD. We consider this population to have prodromal PD. However, in past studies, cases in this cohort had a selection bias as both a clinical syndrome in between no motor deficits and PD, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in this study, we only based inclusion on a clinical phenotype intermediate between no motor impairment and PD. Then, we divided this group further based upon whether or not they had a synucleinopathy. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation, loss of TH-phenotype in the substantia nigra and putamen, and changes in axonal transport occur equally in groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8-expressing phospho-tau, a pathology not seen in the nigrostriatal system of aged-matched controls. These finding were confirmed with early (CP13) and late (PHF1) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and is likely tau mediated.

pathology↗

bioRxiv2020

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

Missense mutations in the LRRK2 gene that lead to LRRK2 kinase hyperactivity can cause Parkinsons disease (PD). The link between LRRK2 and -synuclein aggregation in PD remains enigmatic. Numerous reports suggest critical LRRK2 functions in microglial responses. Herein, we find that LRRK2-positive immune cells in the brain represent CD68-positive pro-inflammatory, monocyte-derived macrophages, distinct from microglia. Rod -synuclein fibrils stimulate LRRK2 kinase activity in monocyte-derived macrophages, and LRRK2 mutations lead to enhanced recruitment of classical monocytes into the midbrain in response to -synuclein. LRRK2 kinase inhibition blocks -synuclein fibril induction of LRRK2 protein in both human and murine macrophages, with human cells demonstrating much higher LRRK2 levels and kinase activity than equivalent murine cells. Further, interferon-{gamma} strongly induces LRRK2 kinase activity in primary human macrophages in comparison to weak effects observed in murine cells. These results highlight peripheral immune responses in LRRK2-linked paradigms that further connect two central proteins in PD.

neuroscience↗