The project REMIND investigated the role of microglia in the pathogenesis of neurodegeneration, with a focus on activity-dependent refinement of synapses, and relevance of risk variants associated to neurodegeneration. The main research objectives achieved under this project can be summarized as follows:
• The role of the AD risk gene INPP5D as a modulator of microglia in early brain development:
We showed that SHIP1 is enriched in early stages of healthy brain development. Combining in vivo loss-of-function approaches and proteomics, we discovered that mice lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered signatures and abnormal synaptic pruning, dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally, but not at later stages. iPSC-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. This work has been recently published in Immunity Cell Press (Matera, Compagnion et al., 2025) and presented at several international conferences.
In addition, we have expanded our studies on SHIP1 investigating potential pharmacological approaches. In collaboration with the group of Prof. Kerr, SUNY University USA, we have developed and characterized a novel small molecule SHIP1 agonist. Our studies in microglia describe a positive effect on intracellular degradation of lipid laden cargos, in association with reduced inflammatory response. These findings have been published (Pedicone, Fernandes, Matera et al., 2022) and further studies are ongoing to test the beneficial effects of this approach in neurodegenerative contexts.
• The role of TDP-43 in modulating microglial function:
TDP-43 proteinopathy is a hallmark of neurodegenerative disorders. Mislocalization of TDP-43 has been observed in neurons and glial cells. However, the role of TDP-43 in microglia and the consequences of its loss-of-function remain unexplored. In this study, we utilized magnetic resonance imaging, confocal, and electron microscopy and uncovered early structural changes and myelin abnormalities in mice lacking microglial TDP-43. Spatial transcriptomics further revealed an enriched interferon-response signature associated with oligodendrocyte dysfunction. Early microglial TDP-43 depletion resulted in motor behavior deficits in adult mice. Mechanistically, knocking out TDP-43 impaired microglial ability to engulf and degrade myelin. It also led to cryptic exon inclusion in the Tyrobp mRNA, resulting in a C-terminally truncated protein causing defective TREM2 signaling. Our findings reveal a novel role for TDP-43 in regulating the TREM2-TYROBP axis in mice, highlighting a previously unrecognized mechanism by which microglial dysfunction contributes to neurodegeneration. This work is under revision and findings have been presented at several international conferences.
• Microglia and synaptic profiling at early stages in the ArcAbeta AD mouse model.
Using lipidomics, confocal live imaging and functional assays, we showed that synaptosomes isolated from juvenile AD mice are more prone to be eliminated by microglia than controls. Increased synapse engulfment was also confirmed in the hippocampi of P15 AD mice compared to controls. This work, currently in preparation (Ginggen et al.), indicates that synaptic and microglia alterations occur already at early developmental stages in a mouse model of AD long before the onset of symptoms. These findings have been presented at multiple international conferences.
• Finally, we have established a novel in vivo model to induce hindlimb paralysis based on chemical denervation, to assess the implication of microglia in potential circuit refinement. We have characterized the model by behavioral tests and histology and found that the synaptic markers VGAT and PSD95 are reduced and the microglial density and morphology altered. In addition, we use microglia depletion approaches to test the effects on functional recovery. These findings are included in a manuscript in preparation.
Finally, we have developed several international collaborations, focused on microglia-mediated synapse refinement in diverse contexts.
