Pathological and Structural Alterations of the Visual Pathway in APP/PS1 Mice: A Spatiotemporal Analysis.

Background/Objectives: Visual dysfunction emerges during the mild cognitive impairment stage of early Alzheimer's disease (AD). While previous studies have primarily focused on retinal pathology, the early pathological progression across central nodes of the visual pathway remains inadequately characterized. This study examined regional pathological and structural alterations throughout the visual pathway at different disease stages in APP/PS1 transgenic mice aged 3, 6, and 9 months. Methods: Cognitive function was first assessed using novel object recognition and Y-maze tests to stage disease progression. Subsequently, Histological staining was employed to systematically analyze pathological features in the retina, lateral geniculate nucleus (LGN), and primary visual cortex (V1). Evaluated parameters encompassed β-amyloid (Aβ) deposition levels, microglial activation status, total neuronal counts, parvalbumin (PV)-positive neuron numbers, and tissue thickness measurements of the retina and V1. Results: At 6 months, mice exhibited an early symptomatic phenotype with selective spatial working memory deficits while long-term memory remained intact. Pathological analysis revealed concurrent Aβ deposition and microglial activation in V1, retina, and hippocampus by 6 months, whereas comparable LGN changes manifested only at 9 months, demonstrating regional heterogeneity in disease progression. V1 neuronal populations remained stable through 6 months but showed significant reduction by 9 months, though PV-positive neurons were selectively preserved. The LGN exhibited no neuronal loss even at 9 months. Gross structural thickness of both retina and V1 remained unchanged across all timepoints. Conclusions: These findings demonstrate that early visual system pathology in this AD model extends beyond the retina. The primary visual cortex exhibits early pathological changes (Aβ deposition and neuroinflammation) concurrent with hippocampal involvement, progressing to selective neuronal loss in later stages. The severity and selectivity of V1 pathology surpass those observed in other visual pathway nodes, including the LGN. Thus, V1 could represent not merely an affected region but a promising site for elucidating early cortical AD mechanisms and developing novel diagnostic biomarkers.