Periodic Reporting for period 1 - MATILDA (Microglia As conTroller of braIn metaboLism During Aging)
Reporting period: 2023-01-01 to 2025-06-30
The nervous and the immune systems undergo a continuous cross talk, starting from early development and continuing throughout adulthood and aging. Defects in this cross-talk contribute to neurodevelopmental and neurodegenerative diseases. Microglia are the resident immune cells in the brain and are primarily involved in this bidirectional communication. During brain development, microglia control several key processes, including neurogenesis, myelin formation and synapse homeostasis. We have obtained indications that during the early postnatal period, microglia direct the genetic signature of specific subgroups of hippocampal neurons, shifting them toward defective metabolic and developmental patterns. This process is controlled by the microglial Triggering receptor expressed on myeloid cells 2 (Trem2), a gene associated to Alzheimer’s Disease. We hypothesized that, by causing imbalances during early maturation phases, dysfunctional Trem2 may have a striking impact on the adult brain, making it a more sensitive target for insults occurring during adulthood and aging. The present project, MATILDA, aims to address this possibility. We will map the hippocampal energetic profile on a single-cell basis, in the presence of proper or defective Trem2 expression and we will define through which mechanisms microglia and Trem2 control the neuronal transcriptomic phenotype. Once settled all methods, we will move to the hypothalamus, where the brain areas orchestrating the body energy homeostasis reside. Owing to the presence of transcriptionally heterogeneous neuronal subtypes and to a vast range of non-neuronal cells regulating systemic metabolism, food intake, and body weight, the hypothalamus represents a key structure to investigate the functional interaction of microglia with specific cell types and the outcomes of its dysregulation. We expect to identify novel mechanisms potentially contributing to metabolic decline, offering potential for new therapeutic strategies that could reverse immune-metabolic dysfunctions by modulation of hypothalamic microglial function.
We demonstrated that, in the early postnatal period, mitochondrial and energetic assets of hippocampal neurons are profoundly altered in the absence of microglial Trem2, with neurons displaying impaired oxidative phosphorylation and diminished mitochondrial mass and length 1,2. The Trem2-mediated microglial control of neuronal oxidative phosphorylation occurs in a region-specific manner, being detectable mostly in the CA1 hippocampal region, which expresses Trem2 at a higher extent. Notably, neuronal dysfunctions in CA1 occur also upon partial Trem2 reduction 1. Preliminary analyses of Trem2 expression in the hypothalamus from adult WT mice revealed a significant heterogeneity across different hypothalamic regions, suggesting that Trem2 defects may differently impact distinct hypothalamic nuclei. Novel technologies that we set in the hippocampus to investigate metabolism in a cell-specific manner are currently being applied to hypothalamus expressing proper or reduced levels of Trem2.
1.Tagliatti E., Desiato, G., et al. (2024). Immunity 57, 86-105.e9. https://doi.org/10.1016/j.immuni.2023.12.002(opens in new window).
2.Chen X.-F. and Bu, G. (2024). Immunity 57, 1–3. https://doi.org/10.1016/j.immuni.2023.12.007(opens in new window).
1.Tagliatti E., Desiato, G., et al. (2024). Immunity 57, 86-105.e9. https://doi.org/10.1016/j.immuni.2023.12.002(opens in new window).
2.Chen X.-F. and Bu, G. (2024). Immunity 57, 1–3. https://doi.org/10.1016/j.immuni.2023.12.007(opens in new window).
Our demonstration that Trem2 deficiency impairs transcriptomic and energetic profile of neurons in a region-specific manner has important implications given that neurons limited degree of metabolic flexibility, and defects in the oxidative phosphorylation genes may contribute toward neurodevelopmental and neurodegenerative disorders. By causing imbalances during early maturation phases, dysfunctional Trem2 may impact the adult brain, making it a more sensitive target for insults occurring during adulthood and aging. Also, the fact that even partial reductions of Trem2 expression are sufficient to derange neuron metabolism open the possibility that reduced Trem2, including Trem2 hemizygous missense variants in patients, may result in neuronal metabolic dysfunctions.