Laboratory Introduction

Elucidation of Lysosome Dysfunction and Cell Death Mechanisms in Age-related Macular Degeneration

P.I.;Shoji Notomi ,MD,PhD

Age-related macular degeneration (AMD) is a major cause of visual impairment in the elderly. Recently, the intraocular administration of anti-VEGF drugs has enabled the treatment of macular neovascularization sprouting from the choroidal vessels under the retina and subsequent vascular leakage, which occur in late AMD, namely neovascular AMD. However, there is no therapy for atrophic AMD, which is characterized by degeneration of the retinal pigment epithelial cells (RPE) and the accumulation of drusen.

Drusen are deposits found beneath the basal membrane of the RPE in AMD, containing lipids and cellular debris. The RPE plays a crucial role in phagocytosis and digesting the old photoreceptor outer segment shed in-between photoreceptors and the RPE, and its lysosomal functions are considered essential for maintaining retinal homeostasis (see Figure 1). The most significant risk factor for AMD is aging. We focused on Lysosome-associated membrane protein 2 (LAMP2), which decreases with age, and examined the role of LAMP2 in AMD.

Histopathological examinations for the LAMP2 expression in AMD eyes indicated that LAMP2, which is abundant in the RPE of healthy eyes, was notably reduced in AMD (Notomi S et al. PNAS 2019). Further studies using LAMP2-deficient mice revealed that as these mice aged, they exhibited increased autofluorescence by lipofuscin, along with the accumulation of drusen-like deposits beneath the RPE, namely basal laminar deposits (see Figure 2 and 3). These results suggest that lysosomal dysfunctions with aging could replicate several pathologies observed in AMD. Additionally, using this animal model, we are investigating the retinal pathology regarding oxidative stress and abnormal lipid metabolism.

Clinical research: Morphological Features of the Choroid and Preceding Macular Lesions in Neovascular Age-Related Macular Degeneration

In Asian patients suffering from AMD, some precursor lesions, not only the accumulation of drusen but also pigment epithelial abnormalities, are commonly seen. Recently, with advancements in optical coherence tomography (OCT), it has become possible to image the retina and the deeper choroidal structures. In central serous chorioretinopathy (CSC) and AMD among Asians, it has been recognized that thickening of the choroid and increased vascular permeability are crucial. This condition of choroidal thickening and vascular hyperpermeability is referred to as Pachychoroid, from the Greek pachy- "thick" and choroid "choroid."

Previous hospital-based studies at Kyushu University Hospital revealed how often the precursor lesions, such as drusen and pigment epithelial abnormalities, can progress to neovascular AMD in Japanese. The results indicated that both drusen and pigment epithelial abnormalities often lead to exudative AMD (see Figure 4). When comparing choroidal thickness, the baseline characteristics are quite opposite between drusen and pigment epithelial abnormalities; eyes with drusen had a thinner choroid in older age, whereas eyes with pigment epithelial abnormalities were associated with a thicker choroid (see Figure 5).

Furthermore, swept-source optical coherence tomography (SS-OCT) allows for high-speed, wide-range, and comprehensive analysis of the choroidal structure. Using ultra-wide-field SS-OCT, we analyzed the choroidal thickness in a specific type of AMD, the so-called pachychoroid neovasculopathy (PNV), comparing the posterior pole (central area) to the periphery. The results showed that PNV, unlike typical AMD or PCV, often affected relatively younger patients and exhibited increased thickness in both the posterior pole and the periphery (see Figure 6). However, a closer examination of the proportions revealed that the choroidal thickening is particularly significant in the posterior pole (see Figure 7). The characteristic thickening of the choroid, especially in the posterior pole, was similar to that observed in patients with central serous chorioretinopathy (CSC). Our findings support recent reports and hypotheses suggesting that AMD in Asians may transition from CSC. Thus, the wide-field imaging can expand our understanding in AMD pathology.

Contact E-mail: noutomi.shouji.926@m.kyushu-u.ac.jp

Selected publications

1. Notomi S et al. Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina. Proc Natl Acad Sci U S A. 116(47): 23724-23734 (2019).
2. Lee JJ, Ishihara K, Notomi S et al. Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells. Biochem Biophys Res Commun. 521(2):414-419 (2020).
3. Wu G, Notomi S* et al. LAMP2 deficiency enhances susceptibility to oxidative-stress-induced RPE degeneration. ARVO 2024, Seattle.
4. Ueta T, Ishihara K, Notomi S et al. RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization. Proc Natl Acad Sci U S A. 116(47): 23705-23713 (2019).
5. Notomi S et al. Dynamic increase in extracellular ATP accelerates photoreceptor cell apoptosis via ligation of P2RX7 in subretinal hemorrhage. PLOS ONE. 8:e53338 (2013).
6. Notomi S et al. Drusen and pigment abnormality predict the development of neovascular age-related macular degeneration in Japanese patients. PLOS ONE. 16(7): e0255213 (2021).
7. Notomi S et al. Critical involvement of extracellular ATP acting on P2RX7 purinergic receptors in photoreceptor cell death. Am J Pathol. 179:2798 (2011).
8. Notomi S et al. A case of bullous central serous chorioretinopathy treated with surgical removal of submacular fibrin and subsequent photodynamic therapy under silicone oil. Case Rep Ophthalmol. 2022;13:385-392 (2022).
9. Notomi S et al. Characteristics of retinal pigment epithelium elevations preceding exudative age-related macular degeneration in Japanese. Ophthalmic Res. 66 (1): 108–115 (2022).
10. Fukuda Y, Notomi S* et al. Differences in Central and Peripheral Choroidal Thickness among the Subtypes of Age-Related Macular Degeneration in an Asian Population. J Clin Med. 12(16), 5364 (2023).
11. Fukuda Y, Notomi S* et al. Wide-field choroidal thickness analysis after half-fluence photodynamic therapy combined with intravitreal aflibercept injection in pachychoroid neovasculopathy. J Clin Med 13(6):1608 (2024)
12. Nagata J, Shiose S et al. Clinical characteristics of eyes with neovascular age-related macular degeneration and retinal pigment epithelium tears. J Clin Med. 12(17), 5496 (2023).