T1R2/T1R3 Identified as the Aβ Receptor: A New Mechanism Linking Aβ42/40 Ratio to Neuronal Hyperexcitability in Alzheimer’s Disease

Abstract

Early neuronal hyperexcitability is a hallmark of Alzheimer’s disease (AD) and correlates with cognitive decline. A key diagnostic indicator is the reduction in soluble Aβ42/40 ratio - from ∼10% in cognitively normal individuals to ∼5% in AD - which reliably predicts progression to dementia. Although widely used as a biomarker, whether this ratio plays an active signaling role has remained unclear. Building on our prior finding that T1R3 is required for Aβ25–35–mediated enhancement of voltage-gated sodium current (INa), we now show that the AD-associated 5% Aβ42/40 ratio functions as an active ligand that increases INa, whereas the physiological ∼10% ratio is inert. This effect requires T1R2 and T1R3, but not T1R1, identifying T1R2/T1R3 as the receptor responsible for Aβ ratio sensing. Human cell lines expressing Nav1.1, Nav1.5, or Nav1.6, as well as differentiated SH-SY5Y cells, all respond selectively to the active ratio. Rodent NG108-15 cells are natively insensitive, but expression of human T1R3 confers responsiveness, indicating a human-specific detection mechanism. These findings identify T1R2/T1R3 as the receptor that detects the Aβ42/40 ratio, link early Aβ changes to hyperexcitability, and point to a therapeutic target for restoring early neuronal function. The human-specific nature of this pathway motivates development of humanized T1R2/T1R3 knock-in mice for in vivo validation. Significance Statement In Alzheimer’s disease progression, neuronal hyperexcitability is one of the underlying causes, yet its molecular mechanism remains unknown. Here we report that the pathological Aβ42/40 ratio, a cerebrospinal fluid biomarker of Alzheimer’s disease, enhances voltage-gated sodium current, the major driving force of action potential generation. We identify the receptor responsible for this effect as an extra-oral sweet taste receptor, T1R2/T1R3. This mechanism is human-specific because rodent cells are insensitive to the pathological Aβ42/40 ratio, providing a molecular clue to why rodent models fail to recapitulate early Alzheimer’s disease. These findings identify T1R2/T1R3 as a molecular entry point at which the earliest biochemical change in AD is converted into neuronal dysfunction, making it a valid target for therapeutic intervention.