Abstract
Purpose :
Aging causes an irreversible, cumulative decline in neuronal function. All mammalian retinas lose retinal ganglion cells (RGC) during normal aging. Therapeutic approaches to aging in the visual system are complicated and needed. Here, we show that secreted phosphoprotein 1 (SPP1) acts as a neuroprotective factor that promotes RGC survival and improves visual function in aging.
Methods :
We first used mice with a global deletion of the Spp1 gene (Spp1 KO) to test whether the RGCs in this strain are more susceptible to damage because of age. We then generated a new transgenic mouse line that combines GFP expression from the endogenous Spp1 locus with the incorporation of loxP sites for conditional deletion of the Spp1 gene and activation of red fluorescent protein after cre recombination. This strain was crossed to B6.GFAP-cre mice to generate an astrocyte-specific Spp1 knockout (Spp1 cKO). During normal aging, we tested how RGC numbers and visual function (pattern ERG, visual acuity) were affected by astrocyte-specific knock-out of Spp1. We finally tested whether adeno-associated virus type 2 (AAV2)-mediated overexpression of SPP1 would have a lasting (at least 1 year) anti-aging effect in visual system.
Results :
During aging, Spp1 KO mice lost RGCs faster than wild-type C57BL/6 mice. Spp1 KO mice showed a higher prevalence of degenerating mitochondria in axons and astrocytes. Conditional knock-out of Spp1 in astrocytes accelerated age-related decline in vision. Over-expression of SPP1 by AAV2 in the retina and optic nerve head of normal C57BL/6 mice apparently slowed aging in the visual system, prevented the enlargement of axons and the accumulation of damaged mitochondria. Treatment with AAV2-Spp1 but not with the control vector AAV2-EGFP preserved visual acuity and pERG amplitude and RGC numbers.
Conclusions :
Virus-mediated overexpression of SPP1 in the retina and optic nerve head prevents age-related RGC loss and decline in visual function for at least one year after initiation of treatment.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.