Primate retinal cones express phosphorylated tau associated with neuronal degeneration yet survive in old age

Abstract

Photoreceptor cells have high energy demands and suffer significantly with age. In aged rodents both rods and cones are lost, but in primates there is no evidence for aged cone loss, although their function declines. Here we ask if aged primate cones suffer from reduced function because of declining metabolic ability. Tau is a microtubule associated protein critical for mitochondrial function in neurons. Its phosphorylation is a feature of neuronal degeneration undermining respiration and mitochondrial dynamics. We show that total tau is widely distributed in the primate outer retina with little age-related change, being present in both rods and cones and their processes. However, all cones specifically accumulate phosphorylated tau, which was not seen in rods. The presence of this protein will likely undermine cone cell function. However, tau phosphorylation inhibits apoptosis. These data may explain why aged primate cones have reduced function but appear to be resistant to cell death. Consequently, therapies designed to remove phosphorylated tau may carry the risk of inducing cone photoreceptor cell death and further undermine ageing visual function.

Human Tau Expression Does Not Induce Mouse Retina Neurodegeneration, Suggesting Differential Toxicity of Tau in Brain vs. Retinal Neurons

“…The reason why the response of the blue cone pathway is particularly stronger with hTau is intriguing. Although Tau expression appeared to be weak in mouse photoreceptors in the present study, the phosphorylation of Tau in cones has been proposed to confer resistance to age-associated degeneration in primates (Aboelnour et al, 2017 ). In some conditions, intracellular expression of hTau may be beneficial for the function and survival of cones.…”

“…The degeneration of retinal ganglion cells (RGCs), the output retinal neurons, has been linked to the upregulation of Aβ and phospho-Tau (Blanks et al, 1991 ; Parisi, 2003 ), two molecules that may be responsible for conscious and non-conscious vision impairments in AD. Other retinal cells expressing amyloid precursor protein (APP) and Tau, such as photoreceptors and interneurons, may be affected by AD and thus contribute to visual loss (Elachouri et al, 2015 ; Chiasseu et al, 2016 ; Aboelnour et al, 2017 ). Although the implication of Aβ in retinal dysfunction is well established (La Morgia et al, 2011 , 2017 ; Koronyo-Hamaoui et al, 2011 ), very little is known on the role that Tau may play in the development of visual deficits linked to AD pathogenesis.…”

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

“…In a small number of young and aged primates, total tau expression in the outer retina was observed in the OPL, ONL and inner segment of photoreceptors, whereas AT8-positive pTau was localized predominantly in the OPL and cones (Aboelnour et al, 2017). In older primates, pTau staining in retinal cones also appeared stronger compared with younger animals (Aboelnour et al, 2017). Altogether, it is apparent that tau expression and pTau accumulation may vary across several species commonly used to model human AD, and future studies should aim to elucidate these differences.…”

“…In the UAS-Gal4 drosophila model of AD, species of pTau, phosphorylated at different epitopes to varying degrees and in a cell type-specific manner, have also been detected in both the retina and brain (Grammenoudi et al, 2006). In a small number of young and aged primates, total tau expression in the outer retina was observed in the OPL, ONL and inner segment of photoreceptors, whereas AT8-positive pTau was localized predominantly in the OPL and cones (Aboelnour et al, 2017). In older primates, pTau staining in retinal cones also appeared stronger compared with younger animals (Aboelnour et al, 2017).…”

Fundamental differences in patterns of retinal ageing between primates and mice

“…Even in age related macular degeneration (AMD) where there is progressive central atrophy, cones persist at the margin of the atrophic region when surrounding rods have died 7 . Their survival may be linked with the specific accumulation of phosphorylated tau in their inner segments that likely undermines mitochondrial function 21 , but which also blocks cell death by reducing cytochrome c release and caspase activity 22 . As cell death is an end point in ageing, such fundamental differences likely reflect mechanisms of ageing that are very different between primates and mice.…”