Neuroprotection of Retinal Ganglion Cells with AAV2-BDNF Pretreatment Restoring Normal TrkB Receptor Protein Levels in Glaucoma

International Journal of Molecular Sciences

Olga Gajewska-Woźniak¹  Małgorzata Skup¹  PawełM. Boguszewski²  Katarzyna Kordecka³  Wioletta Waleszczyk³  Anna Wójcik-Gryciuk³ 

[1] Group of Restorative Neurobiology, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;Laboratory of Behavioral Methods, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;Laboratory of Neurobiology of Vision, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland;

关键词: retina;    BDNF overexpression;    TrkB receptor downregulation;    trabecular occlusion;    microbeads;   

DOI  :  10.3390/ijms21176262

来源: DOAJ

【 摘 要 】

Intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury (ONI) or laser-induced ocular hypertension (OHT). In models of glaucoma, BDNF therapy can delay or halt RGCs loss, but this protection is time-limited. The decreased efficacy of BDNF supplementation has been in part attributed to BDNF TrkB receptor downregulation. However, whether BDNF overexpression causes TrkB downregulation, impairing long-term BDNF signaling in the retina, has not been conclusively proven. After ONI or OHT, when increased retinal BDNF was detected, a concomitant increase, no change or a decrease in TrkB was reported. We examined quantitatively the retinal concentrations of the TrkB protein in relation to BDNF, in a course of adeno-associated viral vector gene therapy (AAV2-BDNF), using a microbead trabecular occlusion model of glaucoma. We show that unilateral glaucoma, with intraocular pressure ( IOP) increased for five weeks, leads to a bilateral decrease of BDNF in the retina at six weeks, accompanied by up to four-fold TrkB upregulation, while a moderate BDNF overexpression in a glaucomatous eye triggers changes that restore normal TrkB concentrations, driving signaling towards long-term RGCs neuroprotection. We conclude that for glaucoma therapy, the careful selection of the appropriate BDNF concentration is the main factor securing the long-term responsiveness of RGCs and the maintenance of normal TrkB levels.

【 授权许可】

Unknown