Retinal macroglia changes in a triple transgenic mouse model of Alzheimer's disease

Abstract

The retinas of Alzheimer’s disease (AD) patients and transgenic AD animal models display amyloid beta deposits and degeneration of ganglion cells. Little is known, however, about the glial changes in the AD retina. The present study used a triple transgenic mouse model (3xTG-AD), which carries mutated human amyloid precursor protein, tau, and presenilin 1 genes and closely mimics the human brain pathology, to investigate retinal glial changes in AD. AD cognitive symptoms are known to begin in the 3xTG-AD mice at four months of age but plaques and tangles are not seen until six to twelve months. Müller cells in 3xTG-AD animals were GFAP-positive, indicating activation, at the earliest time point investigated, nine months. Astrocyte activation was also suggested in the 3xTG-AD mice by an apparent increase in size and process number. Another glial marker, S100, was expressed by astrocytes in both the non-transgenic (NTG) controls and 3xTG-AD retinas. Labeling was predominantly nuclear in nine month non-transgenic (NTG) control mice but was also seen in the cytoplasm and processes at 18 months of age. Interestingly, the nuclear localization was not as prominent in the 3xTG-AD retina even at nine months with labeling observed in astrocyte processes. The diffusion of S100 suggests the possible secretion of this protein, as is seen in the brain, with age and, more profoundly, associated with AD. Several dense, abnormally shaped, opaque structures were noted in all 3xTG-AD mice investigated. These structures, which were enveloped by GFAP and S100-positive astrocytes and Müller cells, were positive for amyloid beta, suggesting that they are amyloid plaques. Staining control retinas with amyloid showed similar structures in 30% of NTG animals but these were fewer in number and not associated with glial activation. The results herein indicate retinal glia activation in the 3xTG-AD mouse retina.

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

“…In line with the above findings, numerous studies examining the retinas of sporadic and transgenic animal models of AD have reported Aβ deposits, vascular Aβ, pTau, and paired helical filament-tau (PHF-tau), often in association with RGC degeneration, local inflammation (i.e., microglial activation), and impairments of retinal structure and function (11,39,40,42,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57).…”

Ocular indicators of Alzheimer’s: exploring disease in the retina

“…These include the Tg2576, APP/PS1, 3xTg, 5xFAD mice, the TgF344-AD rat, and O. degus [1, 46–48, 107, 117, 134, 148, 150, 152, 154, 178, 184]. It has been reported that levels of Aβ 40 and particularly Aβ 42 are elevated in the retina, as well as in the lens, vitreous humor, and choroid of AD rodent models (Table 2) [1, 46, 47, 117, 148, 150, 154, 178, 184].…”

“…Deposits of insoluble Aβ species and subsequent plaque formation have been documented in the retinas of Tg2576, APP SWE /PS1 ΔE9 , APP SWE /PS1 M146L/L286V , 3xTg, and 5xFAD mice, as well as O. degus [1, 46–48, 107, 108, 117, 134, 139, 152, 184, 187, 188]. In the Tg2576 mouse, plaques have been identified most consistently in retinal layers ranging from the GCL to the ONL, and rarely in the photoreceptors and optic nerve [117, 184].…”

Glia-Mediated Retinal Neuroinflammation as a Biomarker in Alzheimer's Disease

“…The immunoreactivity of glial fibrillary acidic protein, usually used as a marker of gliosis, is increased in the ganglion cell layer of retinas from AD patients [69]. Moreover, increased retinal macroglia reactivity, reported as reactive morphology and increased number of astrocytes, was described in a triple transgenic animal model of AD [90]. Regarding microglia, increased expression of MHC II (a marker of microglial reactivity) was described in the retina of AD patients [91].…”