T1R2/T1R3 Identified as the Aβ Receptor: A New Mechanism Linking Aβ42/40 Ratio to Neuronal Hyperexcitability in Alzheimer's Disease
- 1Ion Chat Research Corp.
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 A{beta}42/40 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 A{beta}25-35-mediated enhancement of voltage gated sodium current (INa), we now show that the AD associated 5% A{beta}42/40 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 A{beta} 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 A{beta}42/40 ratio, link early A{beta} 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.
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BibTeX
@misc{saito2026t1r2t1r3,
title = {{T1R2/T1R3 Identified as the Aβ Receptor: A New Mechanism Linking Aβ42/40 Ratio to Neuronal Hyperexcitability in Alzheimer's Disease}},
author = {M. L. Saito and M. R. Saito},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754367},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754367v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - T1R2/T1R3 Identified as the Aβ Receptor: A New Mechanism Linking Aβ42/40 Ratio to Neuronal Hyperexcitability in Alzheimer's Disease
AU - M. L. Saito
AU - M. R. Saito
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754367
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754367v1
AB - 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 A{beta}42/40 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 A{beta}25-35-mediated enhancement of voltage gated sodium current (INa), we now show that the AD associated 5% A{beta}42/40 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 A{beta} 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 A{beta}42/40 ratio, link early A{beta} 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.
ER -