{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Ion Chat Research Corp."
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "M. L. Saito"
    },
    {
      "affs": [
        0
      ],
      "name": "M. R. Saito"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/77cm59ptn21aj.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.25.754367",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754367v1.full",
  "id": "77cm59ptn21aj",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754367v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7215098876",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754367v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-25",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/77cm59ptn21aj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:38Z",
      "native_id": "10.64898/2026.09.25.754367",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.25.754367v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "T1R2/T1R3 Identified as the Aβ Receptor: A New Mechanism Linking Aβ42/40 Ratio to Neuronal Hyperexcitability in Alzheimer's Disease",
  "title_text": "T1R2/T1R3 Identified as the Aβ Receptor: A New Mechanism Linking Aβ42/40 Ratio to Neuronal Hyperexcitability in Alzheimer's Disease",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:38Z",
  "url": "https://research.draconitic.com/paper/77cm59ptn21aj",
  "venue": "bioRxiv",
  "versions": []
}