Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer's disease

Alzheimer's disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole's effect on amyloid beta (A beta) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid beta precursor protein (APP) and presenilin mutations and exhibit early A beta accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced A beta 42, A beta 40, A beta oligomers levels, and A beta plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in NMDA receptor subunits gene expression, which are essential for learning and memory. These data demonstrate that riluzole exerts a disease modifying effect in an A beta mouse model of early-onset familial AD.