Thursday, April 17th, 2025

Time	Event
5:32p	Abnormal Tau Protein Influences Intercellular Mitochondrial Transfer Between Astrocytic and Neuronal Cells Tauopathies are a group of neurodegenerative diseases characterized by the pathological accumulation of abnormal tau protein. A consequence of tau pathologies is mitochondrial dysfunctions, which affect essential processes such as mitochondrial transport, bioenergetics, and dynamics. Given the high energy demands of neurons, tau-induced mitochondrial impairment significantly contributes to neuronal vulnerability and degeneration. Recent studies have revealed that cells can transfer mitochondria between them to help energy-deficient cells. This process, known as intercellular mitochondrial transfer, occurs through two different pathways: an indirect transfer via extracellular vesicles and a direct transfer via tunneling nanotubes and gap junctions. Given the known impact of abnormal tau protein on mitochondrial transport and actin filament dynamics, we hypothesized that intercellular mitochondrial transfer could be altered in the context of tauopathies. Therefore, this study aimed to investigate mitochondrial transfer between astrocytic and neuronal cells and assess how abnormal tau protein may influence this process. Our results showed that abnormal tau protein enhances mitochondrial transfer from astrocytic to neuronal cells. Notably, this transfer occurs mainly via contact-dependent mechanisms. In both pathological and healthy conditions, the transferred astrocytic mitochondria either fused with the mitochondrial network of recipient cells or were degraded in the lysosomes or remained isolated in the cytosol. Our data highlight a novel pathway by which abnormal tau protein impacts mitochondrial function, namely the transfer of astrocytic mitochondria to neuronal cells. (Comment on this)
6:51p	Optimal inter-electrode distances for maximizing single unit yield per electrode in neural recordings State-of-the-art high-density multielectrode arrays enable the recording of simultaneous spiking activity from hundreds of neurons. Although significant efforts have been dedicated to enhancing neural recording devices and developing more efficient sorting algorithms, there has been relatively less focus on the allocation of microelectrodes--a factor that undeniably affects spike sorting effectiveness and ultimately the total number of detected neurons. Here, we systematically examined the relationship between optimal electrode spacing and spike sorting efficiency by creating virtual sparser layouts from high-density recordings through spatial downsampling. We assessed spike sorting performance by comparing the quantity of well-isolated single units per electrode in sparse configurations across various brain regions (neocortex and thalamus) and species (rat, mouse, and human). Enabling the theoretical estimation of optimal electrode arrangements, we complement experimental results with a geometrical modeling framework. Contrary to the general assumption that higher electrode density inherently leads to more efficient sorting, both our theoretical and experimental results reveal a clear optimum for electrode spacing specific to species and regions. We demonstrate that carefully choosing optimal electrode distances could yield a total of 1.7 to 3 times increase in spike sorting efficiency. These findings emphasize the necessity of species- and region-specific microelectrode design optimization. (Comment on this)
6:51p	Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques Anti-amyloid {beta}-peptide (A{beta}) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimers disease. Efficient amyloid plaque clearance has been proven in clinical trials testing anti-A{beta} antibodies, with the impact on cognitive endpoints correlating with the extent of plaque removal. However, treatment is associated with adverse side-effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-A{beta} antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-A{beta} treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model. Mice were treated weekly with anti-A{beta} antibody from 4-8 months of age. Long-term treatment with anti-A{beta} results in a robust and dose-dependent removal of amyloid plaque pathology, with a higher efficiency for removing diffuse over dense-core plaques. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and -Synuclein, as well as immune cell related proteins. Bulk RNA-seq revealed a dose-dependent decrease in brain-wide disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering receptor of myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around remaining plaques remains high regardless of treatment dose. In addition, microglia surrounding remaining plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen presenting and immune signalling proteins. These findings demonstrate that long-term chronic anti-A{beta} mediated removal of A{beta} leads to a dose dependent decrease in brain-wide microglial DAM activation and neurodegeneration, while microglia at residual plaques display a combined DAM and antigen presenting phenotype that suggests a continued treatment response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/645950v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@1b2abe0org.highwire.dtl.DTLVardef@1321ec5org.highwire.dtl.DTLVardef@182267corg.highwire.dtl.DTLVardef@1acba8a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract: Schematic overview of the effects of chronic long-term anti-A treatment in APP-SAA mice Schematic was created with BioRender.com C_FIG (Comment on this)
6:51p	Brain precapillary sphincters modulate myogenic tone in adult and aged mice Brain precapillary sphincters, which are surrounded by contractile pericytes and are located at the junction of penetrating arterioles and first-order capillaries, can increase their diameter by ~30% in a few seconds during sensory stimulation, allowing for rapid control of capillary blood flow over a wide dynamic range. We hypothesized that these properties could help precapillary sphincters maintain the capillary blood flow and shield the downstream capillaries during surges in blood pressure. To test this, we visualized microvessels in adult and old anaesthetized mice using in vivo two-photon microscopy. We showed that a blood pressure surge disrupts both microvascular myogenic response and neurovascular coupling in both adult and old mice, with old mice exhibiting a more diminished myogenic response. Similarly, laser ablation of contractile pericytes encircling precapillary sphincters disrupted neurovascular coupling and myogenic response. The resistance provided by precapillary sphincters may be increasingly important in old mice, where we found changes in the topology of microvessels, potentially affecting microvascular blood flow. Old mice displayed more tortuous penetrating arterioles, reduced pial collateral arteriolar density and altered capillary densities: reduced in the arterial end and increased in the venous end. Our results illustrate how blood pressure surges affect brain microvascular function, underscore the protective role of precapillary sphincters during cerebrovascular autoregulation in response to blood pressure surges and compare vascular topology in adult and old mice in vivo. (Comment on this)

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