Age and Alzheimer’s disease gene expression profiles reversed by the glutamate modulator riluzole

Abstract

Alzheimer's disease (AD) and age-related cognitive decline represent a growing health burden and involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, this study characterized the gene expression changes associated with aging in rodents using RNA-sequencing (RNA-seq). The glutamate modulator, riluzole, which was recently shown to improve memory performance in aged rats, prevented many of the hippocampal age-related gene expression changes. A comparison of the effects of riluzole in rats against human AD datasets revealed that many of the genes changes in AD are reversed by riluzole. Expression changes identified by RNA-Seq were validated by qRT-PCR open arrays. Riluzole is known to increase the glutamate transporter EAAT2's ability to scavenge excess glutamate, regulating synaptic transmission. RNA-seq and immunohistochemistry confirmed an increase in EAAT2 expression in hippocampus, identifying a possible mechanism underlying the improved memory function after riluzole treatment.

Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

“…CK1δ inhibitors are able to restore the correct nuclear localization of TDP‐43, and thus riluzole itself modulating CK1δ activity could ensure the physiological processing and maturation of specific mRNA transcripts, mediated by TDP‐43 . This hypothesis found an experimental confirmation in two independent studies: in the first, riluzole showed the ability to reverse cocaine‐induced suppression of the glutamate transporter EAAT2 in the nucleus accumbens (NAc), and coherently, in the second study, long‐term riluzole administration rescued EAAT2 mRNA levels and protein expression in the hippocampus . Moreover, in a murine model, depletion of EAAT2 promoted the progressive impairment of glutamate reuptake, with consequent death of motor neurons, muscular weakness, and paralysis conditions similar to those of ALS …”

“…[25] This hypothesis found an experimentalc onfirmation in two independents tudies:i nt he first, riluzole showed the ability to reversec ocaineinduced suppression of the glutamatet ransporter EAAT2 in the nucleusa ccumbens (NAc), and coherently,i nt he second study,l ong-term riluzole administration rescued EAAT2 mRNA levels andp rotein expression in the hippocampus. [26,27] Moreover,i namurine model,d epletion of EAAT2 promoted the progressive impairmento fg lutamate reuptake, with consequent death of motor neurons,muscular weakness, and paralysis conditions similar to those of ALS. [28] All this evidenceallows us to speculate that riluzole, through the inhibition of CK1d,e nsures the physiological nuclearc ompartmentalization of TDP-43, which guaranteest he correct maturation of EAAT2 mRNA transcripts.…”

Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans

“…These genes are GRIN1 (glutamate receptor, ionotropic, N-methyl D-aspartate 1), KCNIP3 (Kv channel interacting protein 3, calsenilin), PTCHD1 (patched domain containing 1), FXYD6 (FXYD domain containing ion transport regulator 6), DLG4 (discs, large homolog 4) and NRG1 (neuregulin 1), as well as two potential regulators ( TCF3 and TCF4 ). GRIN1 , FXYD6 , NRG1 and DLG4 have been associated with schizophrenia (21-24), KCNIP3 with Alzheimer's disease (25), PTCHD1 with autism (26), and NRG1 with psychosis (27). The E-box (5′-CANNTG-3′) motif of the two potential regulators, TCF3 and TCF4 , was found in the promoter region of RGMA , GRIN1 and PTCHD1 .…”

“…C57BL/6J mice have a greater preference for oral self-administration of morphine than three other strains (19). Further co-expression analysis in large brain tissue expression datasets demonstrated significant correlation between the expression of RGMA and that of four genes that have been shown to affect risk for other psychiatric disorders, GRIN1 (schizophrenia) (23), KCNIP3 (Alzheimer's disease) (25), FXYD6 (schizophrenia) (21) and PTCHD1 (autism) (26), as well as two transcription factors TCF3 and TCF4 . The latter gene TCF4 is a schizophrenia-risk gene (28).…”

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

“…In rats, it caused a clustering of dendritic spines, enhancing neuroplasticity, and preventing age-related cognitive decline [67]. Also in rats, multiple genes that are downregulated in AD were upregulated by riluzole: the most upregulated genes were those controlling regulation of synaptic transmission, learning and memory, transmission of nerve impulses, regulation of synapse vesicles, and regulation of synaptic plasticity [68]. Furthermore, riluzole increased the gene expression of the excitatory amino acid transporter, which helps maintain the correct amount of glutamate in the synaptic cleft, and is decreased in both aging and AD.…”