Biology subjects

Malbon, A.

Publications and source records attributed to Malbon, A..

4 recordsLinked to original sources

bioRxiv2025

Amyloid-beta pathology increases synaptic engulfment by glia in feline cognitive dysfunction syndrome: A naturally occurring model of Alzheimer's disease

Feline cognitive dysfunction syndrome (CDS) is an age-related neurodegenerative disorder, comparable to dementia in people, characterised by behavioural changes such as increased vocalisation, altered social interactions, sleep-wake cycle, disorientation and house-soiling. Although the underlying mechanisms remain poorly understood, pathologies similar to those observed in Alzheimers disease (AD), have been identified in the brains of aged or CDS-affected cats, including brain atrophy, neuronal loss, amyloid-beta plaques, tau pathology, and cerebral amyloid angiopathy. Neuroinflammation and synapse loss, other important hallmarks of AD, may also play important roles in feline ageing and CDS, but these are yet to be explored. Several mechanisms of synapse loss have been described in human AD and mouse models of amyloidopathy, including synaptic accumulation of amyloid-beta, and the aberrant induction of synaptic engulfment by microglia and astrocytes. In this study, immunohistochemistry and confocal microscopy were used to examine the parietal cortex of young (n=7), aged (n=10), and CDS-affected (n=8) cats. Linear mixed effect modelling revealed that amyloid-beta accumulates within synapses in the aged and CDS-affected brain. Additionally, in the aged and CDS groups there was microgliosis, astrogliosis and increased synaptic engulfment by microglia and astrocytes in regions with A{beta} plaques. Further, microglia and astrocytes show increased internalisation of amyloid-beta-containing synapses near plaques. These findings suggest that amyloid-beta exerts a pathogenic effect in the feline brain, with mechanisms mirroring those seen in human AD.

neuroscience↗

bioRxiv2023

Emergence and spread of feline infection peritonitis due to a highly pathogenic canine/feline recombinant coronavirus

Cross-species transmission of coronaviruses (CoVs) poses a serious threat to both animal and human health1-3. Whilst the large RNA genome of CoVs shows relatively low mutation rates, recombination within genera is frequently observed and demonstrated4-7. Companion animals are often overlooked in the transmission cycle of viral diseases; however, the close relationship of feline (FCoV) and canine CoV (CCoV) to human hCoV-229E5,8, as well as their susceptibility to SARS-CoV-29 highlight their importance in potential transmission cycles. Whilst recombination between CCoV and FCoV of a large fragment spanning orf1b to M has been previously described5,10, here we report the emergence of a novel, highly pathogenic FCoV-CCoV recombinant responsible for a rapidly spreading outbreak of feline infectious peritonitis (FIP), originating in Cyprus11. The minor recombinant region, spanning spike (S), shows 96.5% sequence identity to the pantropic canine coronavirus NA/09. Infection has rapidly spread, infecting cats of all ages. Development of FIP appears very frequent and sequence identities of samples from cats in different districts of the island is strongly supportive of direct transmission. A near cat-specific deletion in the domain 0 of S is present in >90% of FIP cats. It is unclear as yet whether this deletion is directly associated with disease development and may be linked to a biotype switch12. The domain 0 deletion and several amino acid changes in S, particularly the receptor binding domain, indicate potential changes to receptor binding and cell tropism.

microbiology↗

bioRxiv2021

Treatment with IgM-enriched intravenous immunoglobulins (IgM-IVIg) enhances clearance of stroke-associated bacterial lung infection

Post-stroke infection is a common complication of stroke that is associated with increased mortality and morbidity. We previously found that experimental stroke induces an ablation of multiple sub-populations of B cells and reduced levels of IgM antibody that coincide with the development of spontaneous bacterial pneumonia. Reduced circulating IgM concentrations were also observed in acute stroke patients. The loss of IgM antibody after stroke could be an important determinant of infection susceptibility and highlights this pathway as an important target for intervention. We treated mice with a low (replacement), dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after experimental stroke induced by middle cerebral artery occlusion (MCAO) or sham surgery, then recovered mice for 2 d or 5 d. The effect of treatment on lung bacterial burden, lung pathology, brain infarct volume, antibody levels and both lung and systemic cellular and cytokine immune profiles was determined. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved pathology but did not impact infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO, and treatment also reduced concentrations of pro-inflammatory cytokines in the lung. The effects of MCAO and IgM-IVIg treatment on the immune system were tissue specific as no impact on B cells or mouse immunoglobulins were found within the lung. However, the presence of human immunoglobulins from the IgM-IVIg treatment led to increased total lung immunoglobulin concentration. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced their capability to phagocytose Staphylococcus aureus bioparticles in vitro by increasing opsonisation. Low dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance phagocytic activity. Immunomodulatory effects of IgM-IVIg treatment, including reduced pro-inflammatory cytokine production, may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/472965v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1c8684forg.highwire.dtl.DTLVardef@384688org.highwire.dtl.DTLVardef@9eb7f7org.highwire.dtl.DTLVardef@3fe58e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Differential stromal reprogramming in benign and malignant naturally occurring canine mammary tumours identifies disease-promoting stromal components

The importance of cancer-associated stroma (CAS) for initiation and progression of cancer is well accepted. However, as stromal changes in benign forms of naturally occurring tumours are poorly understood, it remains unclear how CAS from benign and malignant tumours compare. Spontaneous canine mammary tumours are viewed as excellent models of human mammary carcinomas (mCA). We have recently reported highly conserved stromal reprogramming between canine and human mCA based on transcriptome analysis of laser-capture-microdissected FFPE specimen. To identify stromal changes between benign and malignant mammary tumours, we have analysed CAS and matched normal stroma from 13 canine mammary adenomas and compared them to 15 canine mCA. Our analyses revealed distinct stromal reprogramming even in small benign tumours. While similarities in stromal reprogramming exist, the CAS signature clearly distinguished adenomas from mCA, suggesting that it may reliably discriminate between benign and malignant tumours. We identified strongly discriminatory genes and found strong differential enrichment in several hallmark signalling pathways between benign and malignant CAS. The distinction between CAS from adenoma and mCA was further substantiated by differential abundance in cellular composition. Finally, to determine key players in CAS reprograming between adenomas and mCA, a network-based gene screening method identified modules of co-expressing genes with distinct expression profile in benign and malignant CAS, and revealed several hub genes as potential molecular drivers in CAS. Given the relevance of canine CAS as a model for the human disease, our approach identifies potential stromal drivers of tumour malignancy with implications for human mCA.\n\nSummary statementRNAsequencing-based analysis of stromal reprogramming between benign and malignant naturally occurring canine mammary tumours identifies potential molecular drivers in cancer-associated stroma that support tumour growth and malignancy.

cancer biology↗