Viewing Ageing Eyes: Diverse Sites of Amyloid Beta Accumulation in the Ageing Mouse Retina and the Up-Regulation of Macrophages

Abstract

BackgroundAmyloid beta (Aβ) accumulates in the ageing central nervous system and is associated with a number of age-related diseases, including age-related macular degeneration (AMD) in the eye. AMD is characterised by accumulation of extracellular deposits called drusen in which Aβ is a key constituent. Aβ activates the complement cascade and its deposition is associated with activated macrophages. So far, little is known about the quantitative measurements of Aβ accumulation and definitions of its relative sites of ocular deposition in the normal ageing mouse.Methodology/Principal FindingsWe have traced Aβ accumulation quantitatively in the ageing mouse retina using immunohistochemistry and Western blot analysis. We reveal that it is not only deposited at Bruch's membrane and along blood vessels, but unexpectedly, it also coats photoreceptor outer segments. While Aβ is present at all sites of deposition from 3 months of age, it increases markedly from 6 months onward. Progressive accumulation of deposits on outer segments was confirmed with scanning electron microscopy, revealing age-related changes in their morphology. Such progress of accumulation of Aβ on photoreceptor outer segments with age was also confirmed in human retinae using immunohistochemistry. We also chart the macrophage response to increases in Aβ showing up-regulation in their numbers using both confocal laser imaging of the eye in vivo followed by in vitro immunostaining. With age macrophages become bloated with cellular debris including Aβ, however, their increasing numbers fail to stop Aβ accumulation.ConclusionsIncreasing Aβ deposition in blood vessels and Bruch's membrane will impact upon retinal perfusion and clearance of cellular waste products from the outer retina, a region of very high metabolic activity. This accumulation of Aβ may contribute to the 30% reduction of photoreceptors found throughout life and the shortening of those that remain. The coating of Aβ on outer segments may also have an impact upon visual function with age.

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

“…The presence of these cells may be indicative of an attempt to clear Aβ, but it has also been suggested that they may be accomplices in the development of AMD. 98 Recently, we showed that Aβ 1-42 accumulates with age in the OXYS retina, but its level is not elevated at the early stages of retinopathy (age 3 mo, Fig. 5).…”

The Eye As a Biomarker for Alzheimer's Disease

“…These cell classes also express β-secretase and are capable of producing Aβ (for review, see Ratnayaka et al, 2015). In genetically modified mice that have abnormalities in APP processing, Aβ accumulates sporadically within the RGC (Dutescu et al, 2009; Du et al, 2015), in the plexiform layers (Perez et al, 2009), in the nuclear layers (Shimazawa et al, 2008), in blood vessel walls (Liu et al, 2009), Bruch's membrane, outer segments of photoreceptors (Hoh et al, 2010) and within the retinal pigment epithelium (Park et al, 2014). In humans, Hoh et al (2010) also reported that Aβ accumulated in photoreceptor outer segments in post-mortem retina of AD patients.…”

Amyloid beta deposition and phosphorylated tau accumulation are key features in aged choroidal vessels in the complement factor H knock out model of retinal degeneration

“…Deposition of Aβ is common in disease (Weller et al, 1998;Armstrong, 2012;Mendal et al, 2013), but is also a feature of retinal ageing (Hoh Kam et al, 2010;Hoh Kam et al, 2013). Aβ deposition in brain vasculature causes endothelium dependent vasoconstriction (Thomas et al 1996;Townsend et al 2002;Niwa et al2000).…”

“…3 (Johnson et al, 2002;Lundh von Leithner et al, 2009;Hoh Kam et al, 2010;Hoh Kam et al, 2013). BM is part of the outer retinal blood barrier and deposition here is likely to alter outer retinal perfusion arising from the choroid.…”

“…It also shows signs of relatively rapid ageing that are probably linked to its energy consumption. Hence, inflammation and extra-cellular deposition, including that of amyloid beta (Aβ) are found with age (Hoh Kam et al, 2010;Isas et al, 2010). These normal ageing events are associated with a loss of approximately 30% in the rod photoreceptor population (Curcio et al, 2001;Cunea and Jeffery, 2007).…”