Chronic FMNL2 overexpression is associated with changes in brain histology and exploratory behavior in adult zebrafish

Formin-like protein 2 (FMNL2) has been associated with Alzheimer`s disease and cerebrovascular pathology and regulates gliovascular remodeling following amyloid exposure. However, the consequences of sustained FMNL2 elevation remain unclear. We generated a transgenic zebrafish line expressing human FMNL2 under the her4.1 promoter and examined adult brain histology and behavior under baseline conditions and following acute amyloid-β42 (Aβ42) exposure. Histological analyses assessed FMNL2 immunoreactivity, overlap between the glial marker BLBP and endothelial tight-junction marker ZO1, synaptic vesicle protein SV2 labeling, and microglial counts. Exploratory behavior was evaluated using the novel tank test and free-movement pattern Y-maze. Compared with uninjected wild-type controls, uninjected FMNL2-overexpressing fish showed higher FMNL2 immunoreactivity, lower BLBP-ZO1 overlap, fewer normalized SV2 puncta, and higher counts of total and morphologically activated microglia. Acute Aβ42 exposure in wild-type animals produced changes in the same direction across these histological endpoints. No significant additional histological changes were detected following Aβ42 exposure in the overexpression background. In the novel tank test, uninjected FMNL2-overexpressing fish had a higher composite boldness index than uninjected wild-type controls. These findings indicate that sustained FMNL2 overexpression is associated with histological changes resembling several responses to acute Aβ42 exposure, together with altered exploratory behavior. They support further investigation of persistent FMNL2 elevation as a contributor to altered glial-vascular organization and cellular responses relevant to Alzheimer`s disease.