Post-symptomatic NLRP3 inhibition rescues cognitive impairment and mitigates amyloid and tau driven neurodegeneration.

Emerging evidence has established neuroinflammation as a primary driver of progressive neuronal loss observed across neurodegenerative diseases (NDDs). The NLRP3 inflammasome is a cytosolic immunoprotective danger sensing complex, which when aberrantly activated drives neuroinflammation, propagates amyloid deposition, and neurodegeneration. Herein, we report the therapeutic benefit of NLRP3 inflammasome inhibition in Alzheimer's disease (AD), using a novel and selective brain-penetrant small molecule NLRP3 inhibitor, VEN-02XX, which we profiled in the 5XFAD/Rubicon KO AD model.

Beyond autophagy: LC3-associated phagocytosis and endocytosis.

Noncanonical functions of the autophagy machinery in pathways including LC3-associated phagocytosis and LC3-associated endocytosis have garnered increasing interest in both normal physiology and pathobiology. New discoveries over the past decade of noncanonical uses of the autophagy machinery in these distinct molecular mechanisms have led to robust investigation into the roles of single-membrane LC3 lipidation. Noncanonical autophagy pathways have now been implicated in the regulation of multiple processes ranging from debris clearance, cellular signaling, and immune regulation and inflammation.

Dying by fire: noncanonical functions of autophagy proteins in neuroinflammation and neurodegeneration.

Neuroinflammation and neurodegeneration are key components in the establishment and progression of neurodegenerative diseases including Alzheimer's Disease (AD). Over the past decade increasing evidence is emerging for the use of components of the canonical autophagy machinery in pathways that are characterized by LC3 lipidation yet are distinct from traditional macro-autophagy. One such pathway that utilizes components of the autophagy machinery to target LC3 to endosomes, a process termed LC3-associated endocytosis (LANDO), has recently been identified and regulates neuroinflammation.