Biology subjects

Sandre, M.

Publications and source records attributed to Sandre, M..

3 recordsLinked to original sources

bioRxiv2024

Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes

Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery involved in recognizing these synapses remains unclear, particularly under pathological conditions. Here, we investigated the phagocytic process of astrocytes through individual gene silencing with a druggable gene library. Our study demonstrates that astrocyte- mediated synapse engulfment is regulated by the Atypical chemokine receptor 3 (Ackr3). Mechanistically, we showed that Ackr3 recognizes phosphatidylethanolamine (PE)-bound C-X-C motif chemokine 12 (CXCL12) at synaptic terminals both in vitro and in vivo, thus serving as a novel marker of synaptic dysfunction. Notably, both the receptor and its ligand are upregulated in post- mortem human Alzheimers disease (AD) brains, and AD mouse models. Downregulation of the Ackr3 in AD mice significantly diminishes astrocyte-mediated synaptic elimination, and rescues pathological phenotypes, including synapse loss and cognitive impairment. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in neurodegenerative disease.

neuroscience↗

bioRxiv2022

COVID-19 Neuropathology: evidence for SARS-CoV-2 invasion of Human Brainstem Nuclei

Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, its still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune-mediated mechanisms. Here, we assess neuropathological alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia / respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in specific brainstem nuclei of 5 COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2, the role of SARS-CoV-2 neurotropism in COVID-19 and its long-term sequelae require further investigation.

neuroscience↗

bioRxiv2021

DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson's disease.

Dopamine dyshomeostasis has been acknowledged to be among the determinants of nigrostriatal neuron degeneration in Parkinsons disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the aldehydic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein Synuclein (Syn), whose misfolding and aggregation represent a major trait of PD pathology, triggering Syn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits Syn neuronal accumulation and hampers Syn clearance at synapses and the soma. By combining cellular and in vivo models, we provided evidence that DOPAL-induced Syn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways, specifically at neuronal projections. The resulting progressive decline of neuronal homeostasis leads to dopaminergic neuron loss and motor impairment, corroborating the Syn-DOPAL interplay as an early event in PD neurodegeneration.

neuroscience↗