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

Abstract 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. Aβ 1-42 oligomers were bilaterally microinjected into the dorsal CA1 region of rats, followed by daily riluzole administration for seven days. 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 and attenuated synaptic and dendritic pathology, while increasing Aβ association with astrocytes and microglia in parallel with enhanced CD11b-related recognition and lysosomal processing. Notably, reductions in neuronal Aβ burden were strongly associated with improved learning performance across individual animals. Riluzole also attenuated Aβ-induced neuronal apoptosis, dendritic degeneration, and dendritic spine loss across the dorsal CA1 sublayers, and limited complement-dependent synaptic elimination by microglia. Although Aβ oligomers induced robust recruitment of astrocytes and microglia, riluzole did not suppress glial activation; instead, it promoted morphological remodeling and shifted both astrocytes and microglia toward phenotypes associated with neuroprotection. Together, these findings indicate that coordinated remodeling of glial responses links glutamatergic modulation to enhanced amyloid handling, synaptic stability, and recovery of hippocampus-dependent memory under Aβ oligomer challenge. Significance Statement Soluble Aβ oligomers impair memory by disrupting synapses and altering glial responses in Alzheimer’s disease. Although glial activation is often viewed as detrimental, our findings demonstrate that the functional state of glia is a critical determinant of synaptic and cognitive outcomes. Using an Aβ oligomer–based rat model, we show that the glutamate modulator riluzole restores hippocampus-dependent memory not by suppressing glial recruitment, but by promoting coordinated functional and morphological remodeling of astrocytes and microglia toward phenotypes associated with neuroprotection. These changes are accompanied by enhanced glia-mediated amyloid handling, reduced complement-dependent synaptic elimination, and preservation of dendritic spine integrity. Across individual animals, hippocampus-dependent learning performance was negatively associated with neuronal Aβ burden, linking glial-mediated amyloid handling to behavioral recovery.