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

Abstract

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 (Aβ) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid β precursor protein (APP) and presenilin mutations and exhibit early Aβ accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aβ42, Aβ40, Aβ oligomers levels, and Aβ 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 Aβ mouse model of early-onset familial AD.

Don't forget astrocytes when targeting Alzheimer's disease

“…suggest that NMDA receptor antagonists have limited ability to modulate reactive astrocytes (Okamoto et al, 2018). In agreement with these findings, memantine treatment over 10 days in 10-month-old APPswe mice does not decrease intensity of GFAP+ immunoreactivity, a generic metric of astrocyte reactivity, associated with Aβ plaques (Unger et al, 2006).…”

“…NMDA receptor antagonists do not significantly alter gene expression profiles of AD‐associated astrocytes. After 5 months of treatment with riluzole, another NMDA receptor antagonist, 5X familial AD mice, which have five familial‐associated AD mutations including amyloid precursor protein (APP; K670M/N671L, 1716V, and V717I) and PS1 (M146L and L286V) mutations and result in a highly robust AD phenotype (Oakley et al, ), have significant reductions of Aβ pathology (including decreased APP, Aβ40, Aβ42, and Aβ oligomer production as well as decreases in both the number and size of plaques) and improved memory performance (Okamoto et al, ). However, bulk RNA sequencing of brains from treated mice reveals only a modest return towards physiological astrocyte‐specific transcriptomic expression levels.…”

“…Disease‐associated microglial‐specific expression is reduced towards normal baselines (Keren‐Shaul et al, ), which may indirectly reduce astrocyte reactivity through inhibition of microglia‐mediated neuroinflammation. Although cell type specificities were determined post hoc in these analyses, results suggest that NMDA receptor antagonists have limited ability to modulate reactive astrocytes (Okamoto et al, ). In agreement with these findings, memantine treatment over 10 days in 10‐month‐old APPswe mice does not decrease intensity of GFAP+ immunoreactivity, a generic metric of astrocyte reactivity, associated with Aβ plaques (Unger et al, ).…”

Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

“…Interestingly, riluzole reversed or prevented cognitive decline in aged rodents, and increased dendritic complexity and expression of glial EAAT in the HPC (Pereira et al, 2014(Pereira et al, , 2017. In a mouse model of Alzheimer's disease, riluzole enhanced cognition, reduced amyloid beta pathology, and reversed alterations in NMDAR subunit expression (Okamoto et al, 2018). Collectively, these findings implicate the modulation of Glu homeostasis, and subsequently neurotrophic and neuroprotective effects, in the therapeutic actions of riluzole.…”

Prevention of Alzheimer's disease by treating mild cognitive impairment with combinations chosen from eight available drugs

“…In mice, riluzole decreased the level of hyperphosphorylated tau, which would be expected to decrease deposition of tau protein [69]. In mice transgenic for 5 familial AD mutations, riluzole ameliorated cognitive decline and reduced levels of Aβ40‐42 by ~50% [70]. In that study, riluzole rescued hippocampal expression of both synaptic and extrasynaptic NMDARs.…”