Riluzole shifts glial responses to protect synapses and memory in Aβ oligomer–treated rats

Abstract Background Soluble Aβ 1-42 (amyloid beta) oligomers are potent neurotoxins that disrupt synaptic function, alter glial responses, and lead to memory impairment in Alzheimer’s disease (AD). Riluzole, a glutamate modulator approved for amyotrophic lateral sclerosis, reduces neuronal hyperexcitability, yet its in vivo effects on Aβ oligomer–induced cognitive dysfunction and glial alterations remain incompletely understood. Here, we investigated whether riluzole ameliorates Aβ 1-42 oligomer–induced memory impairment and associated hippocampal pathology. Methods Aβ 1-42 oligomers were bilaterally microinjected into the dorsal CA1 region of freely moving male rats, followed by daily riluzole administration for 7 days. Then, the animals underwent a battery of behavioural tests before being sacrificed for immuno-histochemical studies. Glial engulfment of Aβ and synapse was visualized through multiplex immunohistochemistry combined with super-resolution microscopy and three-dimensional (3D) reconstruction. Results Behavioral analyses revealed that riluzole significantly improved hippocampus-dependent memory, including contextual learning and spatial working memory, without affecting locomotor activity, anxiety-like behavior, or pain sensitivity. At the cellular level, riluzole reduced neuronal Aβ accumulation which was strongly associated with improved learning performance across individual animals. It enhanced robust Aβ internalization and lysosomal processing within astrocytes and microglia. Though Aβ-induced glial recruitment and activation persisted, riluzole enhanced morphological remodeling and shifted glial cells towards neuroprotective phenotype. Riluzole also attenuated Aβ-induced neuronal apoptosis, dendritic degeneration, and dendritic spine loss across the dorsal CA1 sublayers, and limited complement-mediated synaptic elimination by microglia. Conclusion By enhancing glial Aβ clearance and preserving synaptic integrity, riluzole effectively counteracts Aβ-driven cognitive decline. Together, these findings highlight coordinated glial remodeling as a physiologically relevant mechanism at a therapeutically actionable stage of AD.