EVALUATION OF THE THERAPEUTIC POTENTIAL OF GALLEIN IN A NOVEL APP KNOCK-IN MOUSE MODEL OF ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is characterized by β-amyloid (Aβ) accumulation, neuroinflammation, and cognitive and neuropsychiatric alterations. In vitro studies showed that Aβ amplifies its own production through a pathway in which APP acts as a noncanonical receptor coupled to Go/Gβγ. Since gallein, a Gβγ inhibitor, prevented this mechanism, we evaluated its therapeutic potential in vivo. Homozygous App^NL-F;Psen1^P117L knock-in (APP KI) and wild-type C57BL/6 (WT) mice of both sexes were evaluated at 3 and 6 months using the open-field test, elevated plus maze, novel object recognition test, and Y-maze. Between assessments, mice received gallein or vehicle for eight weeks. Locomotor activity, emotional and exploratory behaviors, risk assessment, and episodic, working, and spatial memory were analyzed. APP KI mice displayed early emotional and exploratory alterations consistent with changes in risk assessment, increased novelty-seeking/impulsivity, and reduced sustained exploration before evident cognitive deficits emerged. Gallein reduced exacerbated exploratory activity and partially normalized these responses without clearly improving cognitive performance. These findings indicate that Gβγ inhibition with gallein attenuates early neurobehavioral alterations, suggesting an early therapeutic window and supporting Gβγ as a target for disease-modifying strategies in AD.