One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Abstract

Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer's disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker.

Diffuse brain damage in normal tension glaucoma

“…Overall, mirroring the findings of the visual system, changes in nonvisual brain areas of NTG suggest their independency from the increases in IOP whereas greater AC and FC changes in nonvisual brain areas of POAG with respect to NTG supports the idea that raised IOP would be a worsening factor. In line with this, previous findings on glaucoma animal models showed IOP‐sensitive increase in amyloid beta (Aβ) [Gupta et al, ], whose accrual and spreading occur across the Alzheimer disease brain. However, according to a novel hypothesis, a relevant role in glaucoma would be played not by IOP but rather by a dysfunction of the “glymphatic system,” a brain‐wide paravascular pathway for CSF and interstitial fluid exchange, which might cause an alteration of neurotoxins, including Aβ, with reduced clearance from ON in NTG or, alternatively, an increased production in POAG [Wostyn et al, ].…”

Memantine‐Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma

“…This is significant as there is growing evidence for the involvement of amyloid β accumulation in glaucoma pathology and increasing recognition of mechanistic similarities between these neurodegenerative disorders . In further support of this hypothesis, we recently demonstrated brimonidine‐mediated RGC neuroprotection (an α2‐adrenergic receptor agonist) in the OHT model were mediated in part by a reduction in amyloid β production and promotion of the nonamyloidogenic pathway . Finally, as multiple studies now also link the progression of age‐related macular degeneration (AMD) with amyloid β accumulation, nonamyloidogenic promoting therapies such as, brimonidine and memantine may also provide useful therapies for the treatment of AMD.…”

Altered Large-Scale Brain Functional Connectivity in Ocular Hypertension

“…In this scenario, OHT may be considered a unique model along the glaucoma spectrum, at a stage where no clinical evidence is present and possibly representing a presymptomatic condition, in view of the fact that a percentage (10%) of subjects with untreated OHT develop POAG within 5 years. Previous findings on glaucoma animal models showed an IOP-sensitive increase in amyloid beta (Ab) (Gupta et al, 2016), whose accrual FIGURE 1 | Differences in within-network (short-range) functional connectivity between OHT and NC groups. Yellow shows clusters where the former group has significantly lower functional connectivity than the latter in brain networks (in green), including default mode network (top left), frontoparietal working memory network, (top right), ventral attention network (low left), and salience network (low right).…”