AGS compounds as a novel therapeutic approach in a mouse model of Alzheimer’s disease

Telomerase reverse transcriptase (TERT) protects neurons from oxidative stress and amyloid beta (Aβ) toxicity. Previous studies showed that AGS compounds (novel small tri-aryl molecules) enhance hippocampal TERT, activate Wnt signaling, promote neurotrophin expression, and protect neurons from amyloid beta-induced damage. To assess the effects of AGS in vivo, 5xFAD Alzheimer’s model mice received daily subcutaneous injections of AGS. In the mouse brain, we examined TERT expression, plaque burden, neurogenesis markers, and genes related to inflammation. Cognitive behavior was evaluated using the Y-maze test. TERT expression decreased with age in 5xFAD mice compared to wild type. AGS treatment increased the expression of TERT, GAP43, and NeuN, while reducing the size and number of amyloid beta plaques. It also elevated plaque-clearing enzymes (CD36, CD47, NEP) and decreased COX2 and PSEN-1. Additionally, mice treated with AGS-499 showed improved cognitive performance, as measured by the Y-maze test. These findings emphasize the neuroprotective potential of AGS compounds and support their further investigation as a candidate therapeutic approach for Alzheimer’s disease. This study's limitations include the unknown mechanism behind TERT enhancement, reliance on only one behavioral assay, a treatment period shorter than the mice’s full lifespan, the small group sizes ( n = 3–6 per group), the pooling of data from both sexes, and the use of a familial AD mouse model that might not fully represent sporadic Alzheimer’s disease.