Basic Science and Pathogenesis

Alzheimer's disease (AD) poses a significant challenge in contemporary healthcare, with traditional mouse models often exhibiting prolonged disease progression periods that impede efficient pharmaceutical drug discovery and development.

To address this challenge, we developed the FAD^3T transgenic mouse model, incorporating three mutations (hAPP, hPSEN1, hMAPT) that closely replicate key genetic factors implicated in AD pathogenesis.

The FAD^3T model exhibits phenotypic parallels to human AD patients, with early onset of pathogenic markers. Notably, diagnostic blood markers such as p-Tau181, p-Tau217, Aβ42/40, and neurofilament light chain (NfL) are detectable in the plasma of 1-month-old FAD^3T mice. Elevated levels of phosphorylated Tau (Thr181) are observed in the brain at 1 month of age. Subsequent observations include Aβ deposition and elevated levels of Phospho-Tau (Thr217, Thr231) at 2 months, followed by elevated levels of Phospho-Tau (Ser396, Ser202, Thr205) at 3 months, with all markers progressively intensifying with age. Importantly, cognitive deficits, including spatial learning and memory impairments, manifest at earlier stages in these mice.

Our findings highlight the exceptional fidelity of the FAD^3T model in recapitulating the complex etiology of AD. Compared to traditional AD mouse models, FAD^3T exhibits accelerated disease onset and progression, providing a rapid platform for expediting drug testing cycles, particularly for therapies targeting disease progression. This innovative mouse model represents a transformative tool for enhancing our understanding of AD pathophysiology and facilitating the expedited development of therapeutic strategies.