Browsing by Author "Francelin, Carolina"

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    BACE1 Inhibition Increases Susceptibility to Oxidative Stress by Promoting Mitochondrial Damage
    (MDPI, 2021-09-28) Francelin, Carolina; Mitter, Sayak K.; Qian, Qingwen; Barodia, Sandeep Kumar; Ip, Colin; Qi, Xiaoping; Gu, Hongmei; Quigley, Judith; Goldberg, Matthew S.; Grant, Maria B.; Boulton, Michael E.; Ophthalmology, School of Medicine
    BACE1 is a key enzyme facilitating the generation of neurotoxic β-amyloid (Aβ) peptide. However, given that BACE1 has multiple substrates we explored the importance of BACE1 in the maintenance of retinal pigment epithelial (RPE) cell homeostasis under oxidative stress. Inhibition of BACE1 reduced mitochondrial membrane potential, increased mitochondrial fragmentation, and increased cleaved caspase-3 expression in cells under oxidative stress. BACE1 inhibition also resulted in significantly lower levels of mitochondrial fusion proteins OPA1 and MFN1 suggesting a higher rate of mitochondrial fission while increasing the levels of mitophagic proteins Parkin and PINK1 and autophagosome numbers. In contrast, BACE2 had minimal effect on cellular response to oxidative stress. In summary, our results emphasize the importance of BACE1 in augmenting cellular defense against oxidative stress by protecting mitochondrial dynamics.
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    β-secretase 1 overexpression by AAV-mediated gene delivery prevents retina degeneration in a mouse model of age-related macular degeneration
    (Elsevier, 2023) Qi, Xiaoping; Francelin, Carolina; Mitter, Sayak; Boye, Sanford L.; Gu, Hongmei; Quigley, Judith; Grant, Maria B.; Boulton, Michael E.; Ophthalmology, School of Medicine
    We reported previously that β-site amyloid precursor protein cleaving enzyme (BACE1) is strongly expressed in the normal retina and that BACE1−/− mice develop pathological phenotypes associated with age-related macular degeneration (AMD). BACE1 expression is increased within the neural retina and retinal pigment epithelium (RPE) in AMD donor eyes suggesting that increased BACE1 is compensatory. We observed that AAV-mediated BACE1 overexpression in the RPE was maintained up to 6 months after AAV1-BACE1 administration. No significant changes in normal mouse visual function or retinal morphology were observed with low-dose vector while the high-dose vector demonstrated some early pathology which regressed with time. No increase in β-amyloid was observed. BACE1 overexpression in the RPE of the superoxide dismutase 2 knockdown (SOD2 KD) mouse, which exhibits an AMD-like phenotype, prevented loss of retinal function and retinal pathology, and this was sustained out to 6 months. Furthermore, BACE1 overexpression was able to inhibit oxidative stress, microglial changes, and loss of RPE tight junction integrity (all features of AMD) in SOD2 KD mice. In conclusion, BACE1 plays a key role in retina/RPE homeostasis, and BACE1 overexpression offers a novel therapeutic target in the treatment of AMD.