Pharmacological activation of LANCL2 provides immunometabolic support for the restoration of cognitive function markers in a mouse model of Alzheimer’s disease

LANCL2 is a member of a three-protein family of receptors that acts as the mammalian receptor for abscisic acid (ABA). LANCL2 expression is significantly diminished both with the brains of 3xTg mice as well as human patients with Alzheimer’s disease. Immunologically, LANCL2 expression is closely associated with regulatory CD4+ T cells and their suppressive capacity as well as within microglia. Treatment of mice with ABA improved spatial memory and reduced amyloid beta load. To study the effects of LANCL2 activation in vivo, we created a novel agonist. After 12 weeks of daily oral treatment at 20 mg/kg, LANCL2 activation significantly reduced inflammatory immune cells including neutrophils, Th17 and Th1 cells in 3xTg mice relative to vehicle control. Further, treatment with LANCL2 agonists reduced the expression of key markers in the brain associated with impaired cognitive function to levels observed within age-matched, negative control WT mice. Activation of LANCL2 prevents the polarization of microglia into a reactive phenotype and supports the metabolic demands of amyloid beta phagocytosis. LANCL2 drugs can combat Alzheimer’s disease progression, given that reactive microglia polarization not only diminishes microglial phagocytic capacity but also increases the production of inflammatory cytokines. The LANCL2 pathway’s transformative potential merits development as a promising therapeutic mechanism for Alzheimer’s disease and diverse age-related cognitive impairment.