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bioRxiv · 10.64898/2026.11.09.765478

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

Lyu, C.·Tayran, H.·Bhattarai, P.·Yilmaz, E.·Kizil, C.
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Abstract

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-{beta}42 (A{beta}42) 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 A{beta}42 exposure in wild-type animals produced changes in the same direction across these histological endpoints. No significant additional histological changes were detected following A{beta}42 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 A{beta}42 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.

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Lyu, C., Tayran, H., Bhattarai, P., Yilmaz, E., Kizil, C.. 2026-11-11. Chronic FMNL2 overexpression is associated with changes in brain histology and exploratory behavior in adult zebrafish. https://doi.org/10.64898/2026.11.09.765478

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