The mGluR2/3 agonist xanthurenic acid improves memory, attention, and synaptic deficits by modulating glutamate release in Alzheimer’s disease model

Amyloid-beta (Aβ) aggregation is the key component of neuritic plaques that drives Alzheimer's disease (AD) progression and cognitive decline. Although synaptic dysfunction strongly correlates with cognitive impairment, its underlying mechanisms remain unclear. Recently, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key contributor to AD pathology, and xanthurenic acid (XA), a naturally occurring end-product of the KP, has been implicated in neuroprotection. In this study, we investigated the neuroprotective effects of intranasally administered XA in an Aβ-induced AD mouse model. AD-like pathology was induced in mice by intracerebroventricular injection of Aβ_1-42. The mice received daily intranasal instillation of XA (0.5 μg/5 μL per nostril) for 6 weeks. After XA treatment was completed, the cognitive performance was assessed in behavioral tests, then the mice were euthanized, and the brain were collected for molecular and biochemical analyses. We showed that XA treatment significantly improved the cognitive function of AD mice, and reduced AD-related pathological markers such as APP, Aβ and BACE-1 in the cortex, hippocampus and olfactory bulb. XA treatment also attenuated Aβ-induced oxidative stress through upregulation of the Nrf2/HO-1/SOD1 and key enzymatic antioxidants (GSH, GST, CAT, SOD), while concurrently reducing lipid peroxidation. Furthermore, XA treatment preserved synaptic integrity, evidenced by restoring both pre- and postsynaptic markers (SNAP-25, SYP, SNAP-23, PSD-95) and enhancing signaling via the cAMP-PKA-CREB pathway. Notably, XA differentially modulated metabotropic glutamate receptors, decreasing mGluR2 and increasing mGluR3 expression. In vitro experiments were conducted in APPswe/ind-transfected SH-SY5Y neuroblastoma cells. XA (3-100 µM) dose-dependently improved the cell viability while reducing cytotoxicity and apoptosis. Overall, these results demonstrate that XA confers multifaceted neuroprotection by modulating Aβ pathology, oxidative stress, synaptic function, and glutamatergic signaling, suggesting its potential as a novel therapeutic strategy to mitigate cognitive decline and pathological progression in AD.