Biology subjects

Beiersdorfer, A.

Publications and source records attributed to Beiersdorfer, A..

3 recordsLinked to original sources

bioRxiv2024

GABAB receptors mediate intracellular calcium release in astrocytes of the prefrontal cortex

The prefrontal cortex (PFC) is a cortical brain region whose multifaceted functions are based on a complex interplay between excitatory pyramidal neurons, inhibitory GABAergic interneurons and astrocytes maintaining a fine-tuned excitation/inhibition balance (E/I balance). The regulation of the E/I balance in cortical network is crucial as the disruption leads to impairments in PFC-associated behavior and pathologies. Astrocytes express specific GABA receptors that mediate intracellular Ca2+ signaling upon stimulation by {gamma}-aminobutyric acid (GABA), resulting in the release of gliotransmitters directly impacting information processing. However, the signaling pathway leading to GABA-induced Ca2+ signaling in astrocytes of the PFC is not well understood. Here we took advantage of GLAST-promoter driven GCaMP6s expression in astrocytes to study GABAergic Ca2+ signaling in PFC astrocytes by confocal microscopy. The results show that GABA induces Ca2+ signaling via the stimulation of the metabotropic GABAB receptor in astrocytes. GABAB receptor-mediated Ca2+ signals greatly depend on intracellular Ca2+ stores rather than on extracellular Ca2+. Additionally, antagonists of the PLC/IP3-signaling cascade significantly reduced GABAB receptor-mediated Ca2+ signaling in astrocytes, suggesting that astrocytic GABAB receptors in the PFC are coupled to the Gq-GPCR signaling pathway.

neuroscience↗

bioRxiv2024

Microgliosis, astrogliosis and loss of aquaporin-4 polarity in frontal cortex of COVID-19 patients

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), causing human coronavirus disease 2019 (COVID-19), not only affects the respiratory tract, but also impacts other organs including the brain. A considerable number of COVID-19 patients develop neuropsychiatric symptoms that may linger for weeks and months and contribute to "long-COVID". While the neurological symptoms of COVID-19 are well described, the cellular mechanisms of neurologic disorders attributed to the infection are still enigmatic. Here, we studied the effect of an infection with SARS-CoV-2 on the structure and expression of marker proteins of astrocytes and microglial cells in the frontal cortex of patients who died from COVID-19 in comparison to non-COVID-19 controls. Most of COVID-19 patients had microglial cells with retracted processes and rounded and enlarged cell bodies in both gray and white matter, as visualized by anti-Iba1 staining and confocal fluorescence microscopy. In addition, gray matter astrocytes in COVID-19 patients were frequently labeled by intense anti-GFAP staining, whereas in non-COVID-19 controls, most gray matter astrocytes expressed little GFAP. The most striking difference between astrocytes in COVID-19 patients and controls was found by anti-aquaporin-4 (AQP4) staining. In COVID-19 patients, a large number of gray matter astrocytes showed an increase in AQP4. In addition, AQP4 polarity was lost and AQP4 covered the entire cell, including the cell body and all cell processes, while in controls, AQP4 immunostaining was mainly detected in endfeet around blood vessels and did not visualize the cell body. In summary, our data suggest neuroinflammation upon SARS-CoV-2 infection including microgliosis and astrogliosis, including loss of AQP4 polarity.

neuroscience↗

bioRxiv2023

Astrocytic uptake of posttranslationally modified amyloid-β leads to endolysosomal system disruption and induction of pro-inflammatory signaling

The disruption of astrocytic catabolic processes contributes to the impairment of amyloid-{beta} (A{beta}) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late-onset Alzheimers disease (AD). While it is known that the posttranslational modifications of A{beta} have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N-terminally pyroglutamylated A{beta}3(pE)-42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro-inflammatory cytokine tumor necrosis factor (TNF) and synapse loss. Here we report that A{beta}3(pE)-42, but not A{beta}1-42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics and lysosome-dependent calcium signaling, and upregulates lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NFB). Treatment with a lysosomal protease inhibitor, E64, rescues GFAP upregulation, NFB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro-inflammatory signaling and related synapse loss. Collectively, our data suggest that A{beta}3(pE)-42-induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro-inflammatory signaling and synapse loss, hallmarks of AD-pathology.

neuroscience↗