Biology subjects

Alberdi, E.

Publications and source records attributed to Alberdi, E..

7 recordsLinked to original sources

bioRxiv2025

PKC-dependent MYRF dysregulation links Aβ pathology to oligodendrocyte, myelin and cognitive alterations in Alzheimer's disease

Alzheimers disease (AD) is characterized not only by neuronal loss and synaptic dysfunction but also by emerging evidence of oligodendrocyte and myelin pathology. Amyloid-{beta} (A{beta}), a hallmark of AD, disrupts oligodendrocyte homeostasis through mechanisms that remain poorly understood. Here, we investigated the role of the myelin regulatory factor (MYRF), a transcription factor essential for oligodendrocyte maturation, in AD-related glial dysfunction. Using the 3xTg-AD mouse model, we observed aberrantly induced maturation dynamics and reduced oligodendrocyte lineage cell density at 12 months in the dentate gyrus, accompanied by increased MYRF expression. Interestingly, sustained MYRF overexpression was found to be toxic for oligodendrocytes in vitro. Moreover, in vitro and in vivo experiments further demonstrated that A{beta} exposure elevates MYRF protein levels and enhances its transcriptional activity, pointing to post-translational regulation. Mechanistically, A{beta} impaired GSK3-dependent phosphorylation and Fbxw7-mediated ubiquitination of MYRF, prolonging N-MYRF stability, an effect prevented by PKC inhibition in vitro. Intracerebroventricular infusion of PKC inhibitor Go6983 normalized MYRF levels, restored oligodendrocyte populations and myelin integrity, and improved hippocampal-dependent spatial learning in 3xTg-AD mice, with locomotor activity and anxiety-like behavior remaining unaffected. Together, these findings identify MYRF dysregulation as a mechanistic link between A{beta}/PKC signaling and oligodendrocyte pathology, and highlight PKC inhibition as a potential strategy to restore oligodendroglial function and cognition in AD.

neuroscience↗

bioRxiv2025

Divergent Effects of APOE3 and APOE4 Human Astrocytes on Key Alzheimer's Disease Hallmarks in Chimeric Mice

Despite strong evidence supporting that both astrocytes and apolipoprotein E (APOE) play crucial roles in the pathogenesis and progression of Alzheimers disease (AD), the impact of astrocytes carrying different APOE variants on key AD pathological hallmarks remains largely unknown. To explore such effects in a human relevant context, we generated a chimeric model of AD. We transplanted isogenic APOE3 or APOE4 human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains of AD model mice. We show that at five to six months after transplantation, transplanted cells have differentiated into mature astrocytes (h-astrocytes) that often integrate in upper layers of one cortical hemisphere. APOE3 and APOE4 h-astrocytes differentially express and secrete the APOE protein, which binds to A{beta} plaques with an isoform-dependent affinity. Remarkably, APOE3 h-astrocytes ameliorate A{beta} pathology, Tau pathology and neuritic dystrophy. In contrast, APOE4 h-astrocytes aggravate these AD processes. Moreover, APOE3 and APOE4 h-astrocytes modulate microglia responses to A{beta} pathology in opposite ways. APOE4 h-astrocytes enhance microglia clustering around A{beta} plaques and exacerbate DAM state whereas APOE3 h-astrocytes reduce microglia clustering and induce a more homeostatic state on plaque-associated microglia. These findings highlight a critical contribution of h-astrocytes not only to A{beta} pathology but also to other key AD hallmarks in chimeric mice. In addition, our findings reveal that h-astrocytes with different APOE variants and the different forms of APOE they secrete have a crucial role in AD progression.

neuroscience↗

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↗

bioRxiv2021

A neuron, microglia, and astrocyte triple coculture model to study Alzheimer disease

Glial cells are essential to understand Alzheimers disease (AD) progression, given their role in neuroinflammation and neurodegeneration. There is a need for reliable and easy to manipulate models that allow studying the mechanisms behind neuron and glia communication. Currently available models such as cocultures require complex methodologies and/or might not be affordable for all laboratories. With this in mind, we aimed to establish a straightforward in vitro setting with neurons and glial cells to study AD. We generated a triple co-culture with neurons, microglia and astrocytes. Immunofluorescence, western blot and ELISA techniques were used to characterize the effects of oligomeric A{beta} (oA{beta}) in this model. We found that, in the triple co-culture, microglia increased the expression of anti-inflammatory markers Arginase I and TGF-{beta}1, and reduced pro-inflammatory iNOS and IL-1{beta}, compared with microglia alone. Astrocytes reduced expression of pro-inflammatory A1 markers AMIGO2 and C3, and displayed a ramified morphology resembling physiological conditions. Lastly, neurons increased post-synaptic markers, and developed more and longer branches than in individual primary cultures. Addition of oA{beta} in the triple coculture reduced synaptic markers and increased microglial activation, which are hallmarks of AD. Consequently, we developed a reliable model, where cells better resemble physiological conditions: microglia are less inflammatory, astrocytes are less reactive and neurons display a more mature morphology than in individual primary cultures. Moreover, we were able to recapitulate A{beta}-induced synaptic loss and inflammation. This model emerges as a powerful tool to study neurodegeneration and inflammation in the context of AD and other neurodegenerative diseases. Table of content image O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY Main pointsO_LIIn our model, microglia and astrocytes are less reactive, and neurons have a more mature morphology than in primary cultures. C_LIO_LIoA{beta} reduced synaptic markers and increased microglial activation. C_LIO_LIThis triple co-culture is a reliable tool to study neurodegeneration and gliosis in vitro. C_LI

neuroscience↗

bioRxiv2019

Microglia actively remodels adult hippocampal neurogenesis through the phagocytosis secretome

During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of their intracellular contents. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in mice chronically deficient for two microglial phagocytosis pathways (P2Y12 and MerTK/Axl), but was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of microglial phagocytosis in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia act as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.\n\nGRAPHICAL ABSTRACT

cell biology↗