Evidence of Synaptic and Neurochemical Remodeling in the Retina of Aging Degus

Abstract

Accumulation of amyloid-beta (Aβ) peptides is regarded as the hallmark of neurodegenerative alterations in the brain of Alzheimer's disease (AD) patients. In the eye, accumulation of Aβ peptides has also been suggested to be a trigger of retinal neurodegenerative mechanisms. Some pathological aspects associated with Aβ levels in the brain are synaptic dysfunction, neurochemical remodeling and glial activation, but these changes have not been established in the retina of animals with Aβ accumulation. We have employed the Octodon degus in which Aβ peptides accumulated in the brain and retina as a function of age. This current study investigated microglial morphology, expression of PSD95, synaptophysin, Iba-1 and choline acetyltransferase (ChAT) in the retina of juvenile, young and adult degus using immunolabeling methods. Neurotransmitters glutamate and gamma-aminobutyric acid (GABA) were detected using immunogold labeling and glutamate receptor subunits were quantified using Western blotting. There was an age-related increase in presynaptic and a decrease in post-synaptic retinal proteins in the retinal plexiform layers. Immunolabeling showed changes in microglial morphology characteristic of intermediate stages of activation around the optic nerve head (ONH) and decreasing activation toward the peripheral retina. Neurotransmitter expression pattern changed at juvenile ages but was similar in adults. Collectively, the results suggest that microglial activation, synaptic remodeling and neurotransmitter changes may be consequent to, or parallel to Aβ peptide and phosphorylated tau accumulation in the retina.

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

“…In the South American rodent O. degus, previously reported to develop several spontaneous AD-like pathologies without genetic manipulation, elevated levels of pTau were primarily detected in the GCL to NFL regions of the retina in both adult and aged animals (Du et al, 2015). In a subsequent study by the same group, early punctate AT8 immunoreactivity in the IPL was reported in young degus, compared with the denser expression in IPL to NFL of juvenile and adult animals (Chang et al, 2020). Interestingly, p(tau)-positive aggregates both appeared and propagated to other inner retinal layers earlier than Aβ deposits in these animals (Chang et al, 2020).…”

“…In a subsequent study by the same group, early punctate AT8 immunoreactivity in the IPL was reported in young degus, compared with the denser expression in IPL to NFL of juvenile and adult animals (Chang et al, 2020). Interestingly, p(tau)-positive aggregates both appeared and propagated to other inner retinal layers earlier than Aβ deposits in these animals (Chang et al, 2020). Similarly, retinal accumulation of total tau and epitope-specific hyperphosphorylation were also reported to precede onset of behavioral deficits and brain tauopathy as early as 3 months of age in the 3xTg mouse model of AD (Chiasseu et al, 2017).…”

“…Studies in this model have demonstrated the presence of Aβ 42 in ocular tissues including the retina as well as increases in Aβ 40 in the RPE (Park et al, 2014;Parthasarathy et al, 2015;Hadoux et al, 2019). In the sporadic O. degus model of AD, Aβ deposition appears to be progressive, accumulating first in the GCL, NFL, INL and photoreceptors (Chang et al, 2020). Whole Increased APP, Aβ, Aβ 42 toxicity Finelli et al, 2004;Greeve et al, 2004;Carmine-Simmen et al, 2009;Cutler et al, 2015 Mouse Tg2576, hTgAPP tg/tg , APP SWE /PS1 E9 , APP SWE /PS1 M146L/L286V , 3xTg, 5xFAD, Tg-SwDI Increased APP, Aβ deposits, Aβ 42 , Aβ 40 , vascular Aβ, Aβ oligomers Ning et al, 2008;Dutescu et al, 2009;Liu et al, 2009;Perez et al, 2009;Alexandrov et al, 2011;Koronyo-Hamaoui et al, 2011;Koronyo et al, 2012;Williams et al, 2013;Yang et al, 2013;Zhao et al, 2013;Edwards et al, 2014;He et al, 2014;Park et al, 2014;Gao et al, 2015;More and Vince, 2015;Parthasarathy et al, 2015;Pogue et al, 2015;Gupta et al, 2016;Oliveira-Souza et al, 2017;Criscuolo et al, 2018;Hadoux et al, 2019;Habiba et al, 2020;Sidiqi et al, 2020 O. degus Spontaneous Increased APP, Aβ, Aβ oligomers Inestrosa et al, 2005;Ardiles et al, 2012;Du et al, 2015 Rat TgF344-AD Increased Aβ Tsai et al, 2014 NFT or pTau related Drosophila hTau Accumulation of pTau Grammenoudi et al, 2006;…”

“…Accumulation of pTau, NFT Liu et al, 2009;Schön et al, 2012;Yang et al, 2013;Zhao et al, 2013;Chiasseu et al, 2017;Grimaldi et al, 2018;Harrison et al, 2019 O. degus Spontaneous Accumulation of pTau Du et al, 2015;Chang et al, 2020 APP, amyloid precursor protein; Aβ, amyloid-beta; pTau, phosphorylated Tau; NFT, neurofibrillary tangle; O. degus, Octodon Degus.…”

Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

“…Beyond the brain, a growing number of studies have provided evidence for AD‐specific protein aggregation, vascular pathology, and markers of neuroinflammation in the neurosensory retina of various transgenic, induced, and spontaneous animal models of AD (Chang et al, 2020; Chiasseu et al, 2017; Do et al, 2019; Doustar et al, 2017; Grimaldi et al, 2018; Hampel et al, 2018; Hart et al, 2016; Koronyo et al, 2012; Lei et al, 2017), as well as in human AD patients (Alexandrov et al, 2011; den Haan et al, 2018; Hadoux et al, 2019; Koronyo et al, 2017; Koronyo‐Hamaoui et al, 2011; La Morgia et al, 2016; Schon et al, 2012; Schultz et al, 2020; Shi et al, 2020; Tsai et al, 2014). Biochemical analyses of Aβ 40 and Aβ 42 peptide levels in retinal and brain tissues from several transgenic murine models and AD patients revealed increases in both peptides in the AD retina as compared to controls, with higher levels in the brain and correlations with brain levels (La Morgia et al, 2016; Schultz et al, 2020; Shi et al, 2020).…”