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Fred Ross-Cisneros, Chiara La Morgia, Billy Pan, Jens Hannibal, Valerio Carelli, Alfredo Sadun; A Histopathologic and Morphometric Analysis of Degenerating Melanopsin Retinal Ganglion Cells in Alzheimer’s Disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):299.
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© ARVO (1962-2015); The Authors (2016-present)
Circadian dysfunction is reported in Alzheimer’s disease (AD), even in its earliest stages. Melanopsin retinal ganglion cells (mRGCs) contribute to circadian photoentrainment. In this study we aimed at characterizing mRGCs in post-mortem AD eyes and optic nerves compared to age-matched controls using histopathologic and morphometric techniques.
Eyes and optic nerves from 14 AD patients (age range from 51-98 years, 7 male and 7 female) and 13 age-matched controls (age range from 54-105 years, 9 males and 4 females) were obtained at necropsy. All AD patients were previously staged neuropathologically with a Braak stage of 5 or higher, which classified them as definite AD cases. An anti-human melanopsin antibody was used to identify, characterize, and count mRGCs on five 5µm thick formalin-fixed paraffin embedded retinal sections (1 for every 5 serial sections) taken sagittally through the optic nerve head with temporal-nasal orientation. The total retinal surface of the 5 sections was calculated and density of mRGCs was determined. The total number of myelinated axons was evaluated for the control and AD cases on retrobulbar plastic-embedded optic nerve cross-sections staining for myelin with p-phenylenediamine.
Qualitative immunohistochemical analysis of the retinas revealed abnormal mRGC morphology in the AD group. There appeared to be “clumping” of the melanopsin in the cell bodies and thinning and fragmentation of dendrites and axons. We found a significant loss of mRGCs in the AD group across all ages as compared to controls (p=0.002) who showed an age-related loss of mRGCs (p=0.02). Further, we demonstrated a trend towards axonal loss in AD compared to controls. Total axon numbers (reflecting almost entirely regular RGCs) in both AD (p=0.01) and controls (p=0.001) showed an age-relate decline, but the AD group showed a faster progression and magnitude of loss.
This study demonstrates a significant loss of mRGCs in the AD group compared to controls. This loss of mRGCs remains fairly constant across all decades in AD group. We also observed what appears to be an age-related loss of regular RGCs in both groups. The AD pathology seems to affect mRGCs independently from the aging process. The observed mRGC loss in AD compared to controls may contribute to the circadian dysfunction described in AD.
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