Abstract / Summary
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.