A role for extracellular vesicles in neuroinflammation associated to frontotemporal dementia

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Focal neurodegeneration in the frontotemporal lobes of the human brain accounts for the clinical manifestations in frontotemporal dementia (FTD), while gliosis account more for the spreading of pathology and the progression of the disease. Indeed, later stages of FTD are characterized by a substantial, widespread and unresolved microgliosis that is conceivably a result of the spread of neuroinflammation. Despite strong evidence showing glial involvement, the mechanisms underpinning the onset and progression of neuroinflammation and the contribution of glia cells in to the neurodegeneration in FTD are poorly understood. The most common FTD-causative genetic mutation is an intronic hexanucleotide -(GGGGCC)n- repeat expansion occurring in the C9orf72 gene. The same intronic expansion is shared by a subset of amyotrophic lateral sclerosis (ALS) patients, who display motor neuron degeneration related symptoms, which may or may not appear along with the FTD clinical manifestations. C9orf72, in complex with its protein binding partners, SMCR8 and WDR41, is known to regulated lysosomes biogenesis, autophagosomes formation and trafficking of vesicles. In the CNS, the omnidirectional exchange of extracellular vesicles (EVs) is tied to modulation of microgliosis, astrogliosis and to oligodendrocytes maturation. In in vivo models, EVs derived from pro- inflammatory activated microglia can spread the inflammatory status. EVs’ contribution to disease progression has been described in Alzheimer’s disease, ALS, Huntington’s disease, multiple sclerosis, Parkinson’s disease, prion disease, and traumatic brain injury. Conversely, EVs derived from stem cells can mitigate microgliosis and revert the neuroinflammation. In this proposal, we hypothesize that C9orf72 haploinsufficiency, a phenotype reported in C9orf72-linked FTD and ALS patients, defines a new role for EVs in disease. Brain EVs in a C9orf72 deficient background have the potential to drive the progression of neuroinflammation. We will test this hypothesis using human cerebral organoid models cultured from deficient or normal C9orf72 genotypes. We will also assess the therapeutic potential of stem cell derived EVs in treating the progression of neuroinflammation in these models.