Ocular-brain co-immunotherapy targeting amyloid-beta in Alzheimer’s disease: Challenges and promising therapeutic avenues

Ocular-brain co-immunotherapy targeting amyloid-beta in Alzheimer's disease: Challenges and promising therapeutic avenuesAlzheimer's disease is an ocular-brain comorbidity: Alzheimer's disease (AD) is a leading neurodegenerative disorder affecting the central nervous system (CNS), clinically characterized by progressive cognitive decline, neuropsychiatric disturbances, and memory deficits.Around 60%-70% of dementia cases are due to AD, making it the most prevalent form.Current estimates suggest that approximately 50 million individuals globally are affected by AD, and the number of dementia patients is expected to rise to 139 million in 2050, with the cost of care projected to increase to nearly $1 trillion (Guo et al., 2024).The pathological hallmarks of AD predominantly consist of senile plaques, resulting from the accumulation of amyloid-beta (Aβ), and neurofibrillary tangles, arising from the hyperphosphorylation of tau protein.These features are accompanied by neuroinflammation, synaptic damage, and neuronal loss.AD is an ocular-brain comorbidity.During embryogenesis, both the retina and the brain develop from the neuroectoderm, resulting in shared anatomical, physiological, and embryological characteristics, including similarities in cell types, vasculature, and immune responses.The retina maintains structural and functional connections with the brain via the optic nerve, which links to the thalamus, optic radiation, and visual cortex.The deposition of Aβ has been observed in the postmortem eyes of AD patients and in the eyes of animal models of AD (Gaire et al., 2024).Aβ predominantly accumulates along blood vessels in the inner retinal layers, optic nerve axon bundles, meningeal lymphatic vessels of the optic nerve, and periorbital lymphatic vessels (Cao et al., 2024).Retinal Aβ is likely to originate from the brain rather than local retinal metabolism (Cao et al., 2024).Notably, Aβ can migrate from the brain to the eye within 60 minutes.The proposed mechanisms for the transport of Aβ from the brain to the eye encompass several pathways (Figure 1A):(1) Aβ transportation along the subarachnoid space and the optic nerve sheath, with entry into the optic nerve axons via perivascular spaces; (2) axonal transport within the optic nerve directed toward the proximal optic nerve; and (3) diffusion through the perivascular spaces of the central retinal artery into the retina (Cao et al., 2024).The clearance of Aβ in the eye involves multiple processes (Figure 1A): (1) Aβ uptake by retinal ganglion cells, followed by axonal transport through the lamina cribrosa and subsequent clearance via the meningeal lymphatic vessels of the optic nerve sheath and periorbital lymphatics; (2) glymphatic clearance facilitated by aquaporin-4 along the perivascular spaces;(3) phagocytosis and degradation by glial cells, including microglia and astrocytes; and (4) efflux across the bloodretina barrier into the systemic circulation for peripheral metabolism.The efficiency of Aβ clearance is modulated by various factors, including the cranio-ocular pressure gradient, expression levels of aquaporin-4, exposure to light, and the administration of cycloplegic agents (Wang et al., 2020).