engleski

Therapeutic strategies for attenuation of imminent inflammation in Alzheimer's disease

As microglia-derived exosomes containing short tau fibrils activate the NLRP3 inflammasome in neighboring cells and accelerate neurofibrillary propagation, microglial dysfunction can be envisioned as causal for neuronal degeneration in Alzheimer’s disease (AD). In the first part of my talk, I will report some of the recent results from our lab in regard to NLRP1, ASC, gasdermin, caspase-6, and LRP1 protein expression in the hippocampal formation postmortem brain tissue from AD and cognitively healthy controls (HC), their correlation with neuropathological changes, and potential role in early AD pathogenesis. In the second part of my talk, I will try to integrate and interpret recent insights in the field and suggest strategies for attenuation of inflammation in AD. One possibility is to measure levels of plasma microglia-derived exosomes and characterize their cargo proteins in subjects suspected of cognitive and behavioral impairment due to AD. Another possibility is the generation of human-induced pluripotent stem cells from dermal fibroblasts of AD subjects and their in vitro differentiation into neural precursor cells/neurons and hematopoietic progenitor cells/microglia. These cells enable the evaluation of omics differences of microglia from AD and HC and can be also co-cultivated with NPC-derived neurons. Such an approach would also allow experimenting with various strategies to revert induced proinflammatory phenotype using NLRP3 and cathepsin-B inhibitors, non-steroidal anti-inflammatory drugs, and immune selective anti-inflammatory derivatives. Moreover, by preventing exosome biogenesis and secretion using e.g. neticonazole and tipifarnib, AD responders can be selected. The overarching aim of all of these efforts is to predict the extent of neuroinflammation in time, thus enabling personalized anti-inflammatory and anti-exosome (including through the use of BBB crossing nanobodies) treatment.

Alzheimer's disease ; exosomes ; inflammasome ; microglia ; neurofibrillary pathology ; neuroinflammation ; personalized anti-inflammatory treatment ; stem cells

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