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.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by progressive memory loss and cognitive decline[1]
Riluzole treatment reduces amyloid β (Aβ) pathology that inversely correlates with memory performance in 5XFAD mice We utilized multiple methodologies to assess Aβ pathology including immunoblotting for full-length amyloid β precursor protein (APP) estimation, Enzyme-linked immunosorbent assays (ELISAs) for major Aβ toxic isoforms, Aβ 42 and Aβ 40, and Aβ oligomers, qRT-PCR based quantification of human APP mRNA transcripts, and immunohistochemical quantification of amyloid plaque load by thioflavin-S staining, to identify riluzole’s effect on different Aβ isoforms and aggregates that have been shown to have diverse roles in AD pathophysiology[32,33]
An ELISA-based assay for Aβ oligomers showed a significant difference between groups (Fig. 2e; F(2,15) = 12.00, p = 0.0008), with post hoc analysis showing a significant difference between WT and 5XFAD (p = 0.0009) and between 5XFAD and 5XFAD-Riluzole mice (p = 0.0057)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by progressive memory loss and cognitive decline[1]. AD exhibits an accumulation of amyloid plaques, formed of amyloid β (Aβ) peptide, and of neurofibrillary tangles made of abnormally hyperphosphorylated tau protein[2]. Only symptomatic medications are available for AD and there are no pharmacological therapies that alter the progression of the disease. One of the greatest challenges for biomedical science today is to develop a disease-modifying therapy for AD and related neurodegenerative disorders. Riluzole can prevent age-related cognitive decline in rats[4] and in a transgenic mouse model of AD expressing mutant human tau[5]. Clustering of dendritic spines in the hippocampus, which form the post-synaptic component of most excitatory synapses[9], is one potential neuroplastic mechanism underlying
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