Biology subjects

Gaminde-Blasco, A.

Publications and source records attributed to Gaminde-Blasco, A..

3 recordsLinked to original sources

bioRxiv2024

Amyloid beta oligomers dysregulate oligodendrocyte differentiation and myelination via PKC in the zebrafish spinal cord

Amyloid {beta} oligomers (A{beta}o) have been proposed as candidates to induce oligodendrocyte (OL) and myelin dysfunctions in early stages of Alzheimers disease (AD) pathology. Nevertheless, little is known about how A{beta}o affect OL differentiation and myelination in vivo, and the underlying molecular mechanisms. In this study, we explored the effects of a brain intraventricular injection of A{beta}o on OLs and myelin in the developing spinal cord of zebrafish larvae. Using quantitative fluorescent in situ RNA hybridization assays, we demonstrated that A{beta}o altered myrf and mbp mRNA levels and the regional distribution of mbp during larval development, suggesting an early differentiation of OLs. Through live imaging of Tg(myrf:mScarlet) and Tg(mbp:tagRFP) zebrafish lines, both crossed with Tg(olig2:EGFP), we found that A{beta}o increased the number of myrf+ and mbp+ OLs in the dorsal spinal cord at 72 hpf and 5 dpf, respectively, without affecting total cell numbers. Furthermore, A{beta}o also increased the number of myelin sheaths per OL and the number of myelinated axons in the dorsal spinal cord compared to vehicle-injected control animals. Interestingly, the treatment of A{beta}o-injected zebrafish with the pan-PKC inhibitor Go6983 restored the aforementioned alterations in OLs and myelin to control levels. Altogether, not only do we demonstrate that A{beta}o induce a precocious oligodendroglial differentiation leading to dysregulated myelination, but we also identified PKC as a key player in A{beta}o-induced pathology.

neuroscience↗

bioRxiv2024

Amyloid-beta increases MBP and MOBP translation in oligodendrocytes through dysregulation of hnRNP A2 dependent RNA dynamics

Oligodendrocyte dysfunction, myelin degeneration, and white matter structural alterations are critical events in Alzheimers disease (AD) that contribute to cognitive decline. A key hallmark of AD, A{beta} oligomers, disrupt oligodendrocyte and myelin homeostasis, but a comprehensive global analysis of the mechanisms involved is lacking. Here, transcriptomic profiling of A{beta}-exposed oligodendrocytes revealed widespread gene expression changes, particularly affecting pathways related to RNA localisation. Among the genes identified, we focused on Hnrnpa2/b1, the gene encoding the hnRNP A2 protein, which is essential for RNA transport and translation of myelin proteins. We confirmed aberrant upregulation of hnRNP A2 in hippocampal oligodendrocytes from post-mortem human brains of early-stage AD patients, A{beta}-injected mouse hippocampi and A{beta}-treated disrupting cells in vitro. RIP-seq analysis of the hnRNP A2 interactome revealed attenuated interactions with Hnrnpk and Hnrnpa2/b1, while interactions with Mbp and Mobp were enriched, suggesting changes in RNA metabolism of molecules associated with mRNA transport of myelin proteins. A{beta} increased the total number and dynamics of mRNA-containing granules, facilitating local translation of the myelin proteins MBP and MOBP and attenuating Ca2+ signalling. These findings suggest that A{beta} oligomers disrupt RNA metabolism mechanisms crucial for oligodendrocyte myelination through dysregulation of hnRNP A2 and myelin protein levels, potentially affecting oligodendroglia Ca2+ homeostasis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/590214v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@19e046eorg.highwire.dtl.DTLVardef@134f15corg.highwire.dtl.DTLVardef@d1f8aaorg.highwire.dtl.DTLVardef@11c97af_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

molecular biology↗

bioRxiv2023

The nonlinear meccano of hyperactivity in Alzheimer

The pathophysiological process of Alzheimers disease (AD) is believed to begin many years before the formal diagnosis of AD dementia. This protracted preclinical phase offers a crucial window for potential therapeutic interventions, yet its comprehensive characterization remains elusive. Accumulating evidence suggests that amyloid-{beta} (A{beta}) may mediate neuronal hyperactivity in circuit dysfunction in the early stages of AD. At the same time, neural activity can also facilitate A{beta} accumulation through intricate feed-forward interactions, complicating elucidating the conditions governing A{beta}-dependent hyperactivity and its diagnostic utility. In this study, we use biophysical modeling to shed light on such conditions. Our analysis reveals that the inherently nonlinear nature of the underlying molecular interactions can give rise to various modes of hyperactivity emergence. This diversity in the mechanisms of hyperactivity may ultimately account for a spectrum of AD manifestations.

neuroscience↗