Biology subjects

Henstridge, C. M.

Publications and source records attributed to Henstridge, C. M..

4 recordsLinked to original sources

bioRxiv2026

Breakdown in the synaptic vesicle cycle defines early and reversible cortical pathogenesis in ALS

Synaptic failure is considered an early driver of Amyotrophic Lateral Sclerosis (ALS), yet identifying the molecular events initiating synaptic decline remains challenging in end-stage human tissue. Here, we exploit the late involvement of the primary visual cortex (Brodmann Area 17 (BA17)) to investigate early disease-associated changes in human ALS. Structural analyses revealed neuropil compaction, presynaptic terminal shrinkage, and synaptic degeneration despite preservation of local neuronal populations. Deep synaptoneurosome proteomics identified a regional signature characterised by disruption of presynaptic vesicle cycling, which closely resembles early pathological changes observed in the inducible human TDP-43 rNLS8 mouse model. Importantly, suppression of TDP-43 expression in vivo restored these proteomic alterations, highlighting recovery of presynaptic vesicle machinery within preserved synaptic structures. Together, these findings reveal early synaptic pathology as a distinct and potentially reversible stage of ALS neurodegeneration.

neuroscience↗

bioRxiv2023

Novel in vivo TDP-43 stress reporter models to accelerate drug development in ALS.

The development of therapies to combat neurodegenerative diseases is widely recognised as a research priority, with conditions like Alzheimers, Amyotrophic lateral sclerosis (ALS) and Parkinsons set to place an ever-heavier burden on healthcare systems in the near future. Despite recent advances in understanding their molecular basis, there is a lack of suitable early biomarkers to test selected compounds and accelerate their translation to clinical trials. We have investigated the utility of in vivo reporters of cytoprotective pathways (e.g. NRF2, p53) as surrogate early biomarkers of the ALS degenerative disease progression. We hypothesized that cellular stress observed in a model of ALS may precede overt cellular damage and could activate our cytoprotective pathway reporters. To test this hypothesis, we generated novel ALS-reporter mice by crossing the hTDP-43tg model into our oxidative stress/inflammation (Hmox1; NRF2 pathway) and DNA damage (p21; p53 pathway) stress reporter models. Histological analysis of reporter expression in a homozygous hTDP-43tg background demonstrated a time-dependent and tissue-specific activation of the reporters in tissues directly associated with ALS. The activation occurs in Purkinje neurons and other parvalbumin-positive (PV+) cells within the cerebellum of mice, before moderate clinical signs are observed. In addition, reporter expression in hTDP-43tg hom peripheral tissues was not observed at the tested mouse ages (15 and 17 days postnatally). Further work is warranted to determine the specific mechanisms by which TDP-43 accumulation leads to reporter activation and whether therapeutic intervention modulates reporters expression. Our current studies suggest that these reporters may represent a powerful approach to accelerate preclinical studies targeting TDP-43 pathologies. We anticipate the reporter strategy could be of great value in developing treatments for a range of degenerative disorders.

neuroscience↗

bioRxiv2019

Altered synaptic ingestion by human microglia in Alzheimer’s disease

Synapse loss correlates with cognitive decline in Alzheimers disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared to non-disease controls, and that proximity to amyloid-{beta} plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting MFG-E8 function rescued the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation. One-Sentence SummaryGlial cells ingest synapses in Alzheimers disease and antibody treatment reduces this ingestion in cultured human cells.

neuroscience↗

bioRxiv2018

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimers disease (AD) is the lack of understanding of how amyloid beta (A{beta}) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human taus influence on human A{beta}-induced pathology. We find that A{beta} and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.\n\nHighlights- Expression of human familial Alzheimers associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function.\n- Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.\n- These data suggest that A{beta} and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

neuroscience↗