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Gerrits E, Giannini LA, Brouwer N, Melhem S, Seilhean D, Le Ber I, Brainbank Neuro-CEB Neuropathology Network, Kamermans A, Kooij G, de Vries HE, Boddeke EW, Seelaar H, van Swieten JC, Eggen BJ. Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex. Nat Neurosci. 2022 Aug;25(8):1034-1048. Epub 2022 Jul 25 PubMed.
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Cedars-Sinai
FTD is a complex neurodegenerative disorder characterized by neuronal loss in frontal and temporal lobes leading to loss of cognitive, social, and emotional abilities. Heterozygous mutations in progranulin (GRN) generally result in reduced protein levels of progranulin and are among the most common genetic causes of FTD (FTD-GRN). Despite recent advancements in understanding of FTD-GRN disease mechanisms, the relative contribution of different cell types, particularly glial and vascular cells, to pathogenesis is largely unresolved. Additionally, lack of profiling of postmortem tissue from FTD-GRN patients necessitates efforts to fully understand the FTD-GRN pathophysiology.
This manuscript is an important step in this direction because it shows, for the first time, the cellular dysfunction of these “supporting cells” in the brains of FTD-GRN patients. Using single nuclear sequencing from the nuclei isolated from affected (frontal and temporal) and unaffected (occipital) lobes from gray matter of FTD-GRN postmortem tissue, the authors show neurovascular and blood-brain barrier dysfunction in these patients. Apart from cortical degeneration, the brains of these patients show vascular fibrosis and altered expression of genes associated with neurovascular cell-cell interactions, and with astrocyte and pericyte function. Surprisingly, the resident immune cells of the brain, microglia, which had been previously implicated in GRN-disease pathogenesis, were only mildly affected.
These critical findings implicate an understudied, underappreciated, but major role of blood-brain barrier and neurovascular dysfunction in FTD. Though neurodegenerative disorders are predominately characterized by neuronal loss that causes their symptoms, the role played by other brain-cell types in disease pathogenesis requires more attention. This study enhances our understanding of the role of such cells in FTD pathophysiology. BBB dysfunction is important because impaired transport of metabolites across the BBB and associated neurovascular dysfunction can have deleterious effects on neuronal health.
The lack of neuroinflammation in FTD-GRN patients came as a surprise, since progranulin gene expression is highest in microglia and studies in mouse models have shown that these cells play a critical role in FTD disease pathogenesis. However, since most studies were done on GRN knockout mice, the mechanisms underlying microgliosis and neuronal loss in mice can be completely different than those observed in humans.
Moving forward, it would be interesting to investigate if similar neurovascular and BBB dysfunctions are observed in FTD patients with mutations in other genes, such as C9ORF72, TBK1, etc., to identify common and variant disease mechanisms. Additionally, it will be highly desirable to model these dysfunctions in patient-derived iPSC cells that can be used to identify early disease mechanisms and test different therapeutics for intervention.
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