ELKHAYARI, A. | Search bioRxiv

bioRxiv2026

m6A modification and prion-like domain proteins converge to dysregulate Neuronal RNA Granules in Alzheimer s disease

Alzheimers disease (AD) is a deadly neurodegenerative disorder with no cure. It is associated with several dysregulated pathways, including axonal transport. The latter supplies synapses with several essential components, including proteins and mRNAs. A proportion of RNAs in neurons is transported from the soma to neuronal extensions along microtubules in highly organized structures, known as Neuronal RNA Granules (NRGs). NRGs have a heterogeneous composition of coding and non-coding RNAs, RNA-binding proteins (RBPs), and components of translational machinery. In this study, we investigate the potential involvement of NRGs in AD pathogenesis, with a particular focus on the N6-methyladenosine (mA), a key RNA modification, and prion-like domain (PrLD) proteins. Our in-silico analysis revealed that a significant portion of mRNAs in NRGs are likely to be highly methylated. Using transcriptomic data from AD brain, we identify dysregulation of key genes in the mA-methylation pathway (METTL3, FTO, YTHDF2/3, eIF3m) as well as PrLD-containing proteins associated with NRGs (STAU2, YBX1). We further observe aberrant expression of mA-methylated mRNAs within both NRGs and synapses. Gene Ontology analysis highlights disruptions in pathways related to NRGs and synaptic function. Together, our findings suggest that impaired NRGs homeostasis may represent a critical and previously underappreciated contributor to AD pathogenesis. By outlining the potential roles of mA and PrLD proteins in regulating NRGs, this work offers a new conceptual framework to better understand AD and identify NRGs as a potential therapeutic target. Finally, we propose a working model illustrating how dysregulation of NRGs homeostasis may drive neurodegeneration in AD.

neuroscience↗

bioRxiv2023

Astrocyte-to-microglia communication via Sema4B-Plexin-B2 modulates injury-induced reactivity of microglia

After central nervous system injury, a rapid cellular and molecular response is induced. This response can be both beneficial and detrimental to neuronal survival in the first few days and increases the risk for neurodegeneration if persistent. Semaphorin4B (Sema4B), a transmembrane protein primarily expressed by cortical astrocytes, has been shown to play a role in neuronal cell death following injury. Our study shows that after cortical stab wound injury, cytokine expression is attenuated in Sema4B knockout mice and microglia/macrophage reactivity is altered. In vitro, Sema4B enhances the reactivity of microglia following injury, suggesting astrocytic Sema4B functions as a ligand. Moreover, injury-induced microglia reactivity is attenuated in the presence of Sema4B knockout astrocytes compared to heterozygous astrocytes. In vitro, experiments indicate Plexin-B2 is the Sema4B receptor on microglia. Consistent with this, in microglia/macrophage-specific Plexin-B2 knockout mice, similar to Sema4B knockout mice, microglial/macrophage reactivity and neuronal cell death are attenuated after cortical injury. Finally, in Sema4B/Plexin-B2 double heterozygous mice, microglial/macrophage reactivity is also reduced after injury, thus supporting the idea that both Sema4B and Plexin-B2 are part of the same signaling pathway. Taken together, we propose a model in which following injury, astrocytic Sema4B enhances the response of microglia/macrophages via Plexin-B2, leading to increased reactivity. Significance statementIn this study, we show that in the brain cortex, Sema4B, a protein mainly expressed by astrocytes, plays a crucial role in enhancing the reactivity of microglia/macrophages via Plexin-B2. These findings reveal new molecular signaling instigated by astrocytes toward microglia/macrophages in the context of central nervous system (CNS) injury, shedding new light on the complex interplay between astrocytes and microglia/macrophages. Taken together, our findings suggest that targeting the Sema4B/Plexin-B2 pathway could be a promising therapeutic approach for reducing microglia reactivity and improving the adaptive response in the context of CNS injury.

neuroscience↗