Biology subjects

Pietrogrande, G.

Publications and source records attributed to Pietrogrande, G..

5 recordsLinked to original sources

bioRxiv2025

Interaction of Gut-Microbial Amyloids with Endogenous Amyloids can Drives Microglial Hyperactivity and Neuroinflammation in Alzheimers Disease

Gut bacteria have emerged as silent drivers in the pathology of Alzheimers disease (AD). They also make amyloids with structure analogue to pathological amyloids and have potential to cross-seed and propagate in a prion-like manner. AD is characterised by the accumulation of mature extracellular Amyloid-{beta} (A{beta}) plaques which are surrounded by inflammatory microglia. We report that exposure to interspecies microbial amyloids of FapC (fimbriae) and CsgA (curli) from opportunistic gut pathogens Pseudomonas aeruginosa and Escherichia coli hyperactivates microglia against A{beta} fibrils. Microbial amyloids and A{beta} fibrils converge in phagocytic compartments through subsequent internalization, not observed with A{beta} fibrils alone. This convergence promotes pro-inflammatory microglia with a defective proteome similar to those observed in AD brains. The resulting clusters develop a pro-inflammatory, indigestible interactome that is eventually regurgitated, inducing progressive degeneration in bystander neurons and ultimately leading to cognitive decline. Collectively, these findings provide compelling evidence that microbial amyloids can trigger progressive AD pathology through microglia-driven neuroinflammation.

cell biology↗

bioRxiv2023

Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs at the expense of neural lineages. We next show that the clinically-approved drug, Rapamycin, inhibits AP1-mediated senescence and restores aberrant NCC differentiation trajectory in human organoids exposed to VPA. Notably, in vivo validation in developing zebrafish highlighted the therapeutic promise of this approach. Collectively our data identifies a novel mechanism for VPA-associated neurodevelopmental teratogenicity and a potential pharmacological preventative strategy. The results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery and safety testing.

neuroscience↗

bioRxiv2023

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology.

Aging is the primary risk factor for most neurodegenerative diseases, and recently coronavirus disease 2019 (COVID-19) has been associated with severe neurological manifestations that can eventually impact neurodegenerative conditions in the long-term. The progressive accumulation of senescent cells in vivo strongly contributes to brain aging and neurodegenerative co-morbidities but the impact of virus-induced senescence in the aetiology of neuropathologies is unknown. Here, we show that senescent cells accumulate in physiologically aged brain organoids of human origin and that senolytic treatment reduces inflammation and cellular senescence; for which we found that combined treatment with the senolytic drugs dasatinib and quercetin rejuvenates transcriptomic human brain aging clocks. We further interrogated brain frontal cortex regions in postmortem patients who succumbed to severe COVID-19 and observed increased accumulation of senescent cells as compared to age-matched control brains from non-COVID-affected individuals. Moreover, we show that exposure of human brain organoids to SARS-CoV-2 evoked cellular senescence, and that spatial transcriptomic sequencing of virus-induced senescent cells identified a unique SARS-CoV-2 variant-specific inflammatory signature that is different from endogenous naturally-emerging senescent cells. Importantly, following SARS-CoV-2 infection of human brain organoids, treatment with senolytics blocked viral retention and prevented the emergence of senescent corticothalamic and GABAergic neurons. Furthermore, we demonstrate in human ACE2 overexpressing mice that senolytic treatment ameliorates COVID-19 brain pathology following infection with SARS-CoV-2. In vivo treatment with senolytics improved SARS-CoV-2 clinical phenotype and survival, alleviated brain senescence and reactive astrogliosis, promoted survival of dopaminergic neurons, and reduced viral and senescence-associated secretory phenotype gene expression in the brain. Collectively, our findings demonstrate SARS-CoV-2 can trigger cellular senescence in the brain, and that senolytic therapy mitigates senescence-driven brain aging and multiple neuropathological sequelae caused by neurotropic viruses, including SARS-CoV-2.

neuroscience↗

bioRxiv2022

Deconstructing replicative senescence heterogeneity of human mesenchymal stem cells at single cell resolution reveals therapeutically targetable senescent cell sub-populations

Cellular senescence is characterised by a state of permanent cell cycle arrest. It is accompanied by often variable release of the so-called senescence-associated secretory phenotype (SASP) factors, and occurs in response to a variety of triggers such as persistent DNA damage, telomere dysfunction, or oncogene activation. While cellular senescence is a recognised driver of organismal ageing, the extent of heterogeneity within and between different senescent cell populations remains largely unclear. Elucidating the drivers and extent of variability in cellular senescence states is important for discovering novel targeted seno-therapeutics and for overcoming cell expansion constraints in the cell therapy industry. Here we combine cell biological and single cell RNA-sequencing approaches to investigate heterogeneity of replicative senescence in human ESC-derived mesenchymal stem cells (esMSCs) as MSCs are the cell type of choice for the majority of current stem cell therapies and senescence of MSC is a recognized driver of organismal ageing. Our data identify three senescent subpopulations in the senescing esMSC population that differ in SASP, oncogene expression, and escape from senescence. Uncovering and defining this heterogeneity of senescence states in cultured human esMSCs allowed us to identify potential drug targets that may delay the emergence of senescent MSCs in vitro and perhaps in vivo in the future.

bioinformatics↗

bioRxiv2018

Low oxygen post conditioning improves stroke-induced cognitive impairment

Post-stroke cognitive impairment has proven to be notoriously difficult to treat. In the current study, we sought to both better understand cellular changes that underpin cognitive deficits and to consider the potential restorative benefits of low oxygen post conditioning (LOPC). We were motivated to use LOPC as an intervention as it is one of the few experimental interventions previously shown to improve cognitive function post-stroke. Experimental stroke was induced by photothrombotic occlusion in adult male C57BL/6 mice. Mice were randomly assigned to either a normal atmospheric air exposure or low oxygen (11% O2) exposure groups three days post-occlusion. On day 17 post-stroke, mice were euthanized for histology or biochemical analyses. Stroked mice exposed to LOPC was associated with marked reductions in amyloid-beta both in its absolute level and in the extent of its oligomerization. Exposure to LOPC post-stroke also improved cellular deficits induced by stroke including an increase in vessel density, a reduction in vascular leakage, and restoration of AQP4 polarisation. Critically, stroked mice exposed to LOPC exhibited robust improvements in cognitive function post-stroke, assessed using a touchscreen based paired-associate learning task. These findings provide compelling pre-clinical evidence of the potential clinical utility of LOPC for enhancing recovery post-stroke.

neuroscience↗