Biology subjects

D'Brant, L.

Publications and source records attributed to D'Brant, L..

4 recordsLinked to original sources

bioRxiv2024

HSV-1 Infection Alters MAPT Splicing and Promotes Tau Pathology in Neural Models of Alzheimer's Disease

INTRODUCTIONHerpes simplex virus 1 (HSV-1) infection alters critical markers of Alzheimers Disease (AD) in neurons. One key marker of AD is the hyperphosphorylation of Tau, accompanied by altered levels of Tau isoforms. However, an imbalance in these Tau splice variants, specifically resulting from altered 3R to 4R MAPT splicing of exon 10, has yet to be directly associated with HSV-1 infection METHODSTo this end, we infected 2D and 3D human neural models with HSV-1 and monitored MAPT splicing and Tau phosphorylation. Further, we transduced SH-SY5Y-neurons with HSV-1 ICP27 which alters RNA splicing to analyze if ICP27 alone is sufficient to induce altered MAPT exon 10 splicing. RESULTSWe show that HSV-1 infection induces altered splicing of MAPT exon 10, increasing 4R-Tau protein levels, Tau hyperphosphorylation, and Tau oligomerization. DISCUSSIONOur experiments reveal a novel link between HSV-1 infection and the development of cytopathic phenotypes linked with AD progression. HIGHLIGHTSO_LIHSV-1 infection in forebrain organoids reduces the neurite length of MAP2-positive neurons. C_LIO_LIHSV-1 infection increases Tau hyperphosphorylation in both two-month-old and four-month-old forebrain organoids. C_LIO_LIHSV-1 infection increases Exon 10 containing (4R) MAPT mRNA and 4R-Tau protein expression in both forebrain organoids and human SH-SY5Y-neurons. C_LIO_LIHSV-1 ICP27 is both necessary and sufficient to induce increased 4R MAPT mRNA and 4R-Tau protein expression in SH-SY5Y-neurons. C_LIO_LIHSV-1 infection increases Tau oligomerization in both forebrain organoids and SH-SY5Y-neurons. C_LI

microbiology↗

bioRxiv2024

Fully Human Bifunctional Intrabodies Achieve Graded Reduction of Intracellular Tau and Rescue Survival of MAPT Mutation iPSC-derived Neurons

Tau protein aggregation is a hallmark of several neurodegenerative diseases, including Alzheimers disease, frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP), spurring development of tau-lowering therapeutic strategies. Here, we report fully human bifunctional anti-tau-PEST intrabodies that bind the mid-domain of tau to block aggregation and degrade tau via the proteasome using the ornithine decarboxylase (ODC) PEST degron. They effectively reduced tau protein in human iPSC-derived cortical neurons in 2D cultures and 3D organoids, including those with the disease-associated tau mutations R5L, N279K, R406W, and V337M. Anti-tau-hPEST intrabodies facilitated efficient ubiquitin-independent proteolysis, in contrast to tau-lowering approaches that rely on the cells ubiquitination system. Importantly, they counteracted the proteasome impairment observed in V337M patient-derived cortical neurons and significantly improved neuronal survival. By serial mutagenesis, we created variants of the PEST degron that achieved graded levels of tau reduction. Moderate reduction was as effective as high reduction against tau V337M-induced neural cell death.

neuroscience↗

bioRxiv2022

Neuronal glutamate transporters control reciprocal inhibition and gain modulation in D1 medium spiny neurons

Understanding the function of glutamate transporters has broad implications for explaining how neurons integrate information and relay it through complex neuronal circuits. Most of what is currently known about glutamate transporters, specifically their ability to maintain glutamate homeostasis and limit glutamate diffusion away from the synaptic cleft, is based on studies of glial glutamate transporters. By contrast, little is known about the functional implications of neuronal glutamate transporters. The neuronal glutamate transporter EAAC1 is widely expressed throughout the brain, particularly in the striatum, the primary input nucleus of the basal ganglia, a region implicated with movement execution and reward. Here, we show that EAAC1 limits synaptic excitation onto a population of striatal medium spiny neurons identified for their expression of D1 dopamine receptors (D1-MSNs). In these cells, EAAC1 also contributes to strengthen lateral inhibition from other D1-MSNs. Together, these effects contribute to reduce the gain of the input-output relationship and increase the offset at increasing levels of synaptic inhibition in D1-MSNs. By reducing the sensitivity and dynamic range of action potential firing in D1-MSNs, EAAC1 limits the propensity of mice to rapidly switch between behaviors associated with different reward probabilities.

neuroscience↗

bioRxiv2019

Beyond the suprachiasmatic nucleus: circadian rhythmicity shapes astrocyte morphology and neuronal function in hippocampal area CA1

Most animal species operate according to a 24-hour period set by the suprachiasmatic nucleus (SCN) of the hypothalamus. The rhythmic activity of the SCN is known to modulate hippocampal-dependent memory processes, but the molecular and cellular mechanisms that account for this effect remain largely unknown. Here, we show that there are cell-type specific structural and functional changes that occur with circadian rhythmicity in neurons and astrocytes in hippocampal area CA1. Pyramidal neurons change the surface expression of NMDA receptors, whereas astrocytes change their proximity to synapses. Together, these phenomena alter glutamate clearance, receptor activation and integration of temporally clustered excitatory synaptic inputs, ultimately shaping hippocampal-dependent learning in vivo. We identify corticosterone as a key contributor to changes in synaptic strength. These findings identify important mechanisms through which neurons and astrocytes modify the molecular composition and structure of the synaptic environment, contribute to the local storage of information in the hippocampus and alter the temporal dynamics of cognitive processing.

neuroscience↗