Pathological alterations, such as synaptic dysfunctions, neuronal cell loss, inflammatory responses, microvasculature abnormalities, mitochondrial failure, and oxidative stress, have been associated with amyloid-beta (Aβ) in the brain. However, similar pathological alterations have more recently also been reported in the retina where they may mirror analogous events occurring in the brain (1). The present review will focus on these aforementioned aspects of Aβ’s deleterious effects but does not have the ambition to cover all aspects of Aβ cytotoxicity. For instance, the issues related to aberrant Aβ clearance will not be discussed here since they have been recently extensively reviewed elsewhere [e.g., Ref. (2)].

Retinal accumulation of Aβ is broadly recognized as being involved in amyloidosis-associated neurodegeneration. Pathological hallmarks of amyloidosis are related to the accumulation of specific types of proteins, including Aβ, prone to oligomerize with a high content of beta (β)-sheet structures (3). Among the neurodegenerative diseases related to Aβ amyloidosis, Alzheimer’s disease (AD) is certainly the best known and the most studied. More recently, it has been recognized that Aβ-related amyloidosis also occurs during glaucoma and age-related macular degeneration (AMD). Historically and up to very recently, AD was considered as an exclusively cerebral disorder, while glaucoma and AMD were regarded as neurodegenerative disorders specific to the retina. However, it is increasingly clear that AD-like pathological alterations seen in the brain also occur in the retina (4), where they may even start earlier. Conversely, the pathological phenomena observed in glaucoma, for example, are associated with neurodegeneration of selected brain areas (5). Altogether, this new evidence suggests that the retina may be used as the “window” to the brain for the study of the earliest pathophysiological changes involved in neurodegeneration. This attractive idea is behind different aspects of amyloidosis that will be discussed here.

Parkinson’s disease (PD), which shares many features of Aβ-amyloidosis with AD, glaucoma, and AMD, will not be discussed here, and we recommend a number of excellent and exhaustive reviews on this topic (6, 7). Indeed, although PD is considered an amyloidosis-associated disease, involving the accumulation of both Aβ and α-synuclein, the relevant fibrils have not been identified in the PD retina (8). This is in sharp contrast with the presence of Aβ plaques, identical to those found in AD-vulnerable brain areas that have been identified in the retina (9, 10). Furthermore, Aβ-amyloidosis seen in PD is sometimes considered as an epiphenomenon to the oligomerization of α-synuclein into structures known as Lewy bodies. Consequently, rigorous analysis of alterations specific to Aβ-amyloidosis in PD would require a systematic comparative follow-up of cohorts composed of “mixed” PD (displaying both α-synuclein and Aβ-amyloidosis) and “pure” PD (displaying exclusively α-synuclein amyloidosis). Such studies, similar to the one reported by Bertrand and colleagues (11), are still relatively scarce. Finally, there is no consensus about the precise type of pathological alterations in the PD retina, since thickening (12), thinning (13), and absence of change (14) in the retinal nerve fiber layer (RNFL) have all been reported. The analysis of retinal Aβ-amyloidosis in PD would therefore be more complicated. By consequence, this review will focus only on AD, glaucoma, and AMD.

Amyloid precursor protein (APP), a type 1 transmembrane glycoprotein, belongs to a family of proteins, which in mammals include APP-like protein-1 (APLP1) and APP-like protein-2 (APLP2) (15). Despite the widespread expression of the APP gene in mammalian and non-mammalian cells, the physiological role of APP is still unclear. APP-related mRNA has been found not only in the nervous system but also in the immune system, muscles, and other organs, such as the pancreas, lung, and kidney (16, 17). Alternative splicing of APP mRNA gives rise to multiple isoforms, which are differentially expressed among various tissues and different stages of development. In particular, APP is upregulated during brain development, and specific APP variants are associated with neurite outgrowth and synaptogenesis (18, 19).

There are three major APP isoforms, APP770, APP751, and APP695, which are all generated from the alternative splicing of exons 7 and/or 8. APP695 is mainly neuronal, whereas the other two variants are principally non-neuronal (20). APP polypeptides undergo posttranslational modifications (such as glycosylation and phosphorylation) and are subsequently addressed to the plasma membrane via the constitutive secretory pathway (Figure 1A). Successively, APP is internalized through clathrin-mediated endocytosis and reaches the endosomal system. Part of endosomal APP is recycled to the cell surface, whereas another conspicuous part is degraded in lysosomes (21, 22). In the steady state, APP is preferentially localized in the Golgi and in the trans-Golgi network, and only a tiny fraction is localized on the cell surface.

Amyloid precursor protein can be posttranslationally processed through two distinct pathways [reviewed in Ref. (23)] (Figure 1B). The amyloidogenic pathway involves sequential cleavage steps by β-secretase and γ-secretase, which generates Aβ. The second pathway, which is predominant, involves sequential cleavage steps by α-secretase and γ-secretase but does not yield Aβ. Indeed, α-secretase cleavage occurs within the Aβ peptide region, preventing Aβ formation. It has been shown that proteases belonging to the A-disintegrin and metalloproteinase (ADAM) family have α-secretase activity (24–26). Since ADAMs are cell surface proteins, α-secretase cleavage likely occurs at the level of the plasma membrane and involves the membrane pool of APP (27). α-secretase cleavage leads to the formation of an amino-terminal fragment called secreted APP (sAPP)α and a carboxy-terminal fragment called CTF83. β-secretase is a type 1 transmembrane protease, and its cleavage leads to the formation of sAPPβ and CTF99. In converse to α-secretase cleavage, β-secretase cleavage occurs mainly in endocytic vesicles and not at the cell surface, where both β-site APP cleaving enzyme-1 (BACE1) and APP are swiftly recycled. The first cleavage step is followed by γ-secretase cleavage in both pathways. The latter is a protein complex composed of at least four proteins: presenilin (PS) 1 or 2, nicastrin, presenilin enhancer 2 (Pen 2), and anterior pharynx defective 1 (Aph-1) (28). γ-secretase processes CTF83 and CTF99, yielding the APP intracellular domain (AICD) plus the fragment p3 and AICD plus Aβ, respectively. Aβ peptides of different lengths, from 38 to 43 amino acids, can be generated by γ-secretase cleavage; however, Aβ1–42 and Aβ1–40 are considered to be the most relevant forms to amyloidosis.

Since APP undergoes sequential cleavage steps, it has been difficult to distinguish the physiological role of APP from those of its cleavage products. Generally, the role of APP in the brain is regarded as beneficial and often associated with its cleavage product, sAPPα. It has been shown that APP promotes cell proliferation, neuronal stem cell differentiation, neurite outgrowth, synaptogenesis, cell adhesion, and regulates long-term potentiation (LTP). APP-KO mice are viable and fertile, suggesting that APP – or its products – are not essential for development or alternatively, are part of a network of proteins with redundant functions (29). However, APP-deficient mice present various abnormalities, such as reduced body and brain size, hypersensitivity to seizures, and impaired learning and LTP. These phenotypes are rescued by the introduction of sAPPα in APP-deficient mice, suggesting that sAPPα may play an important role in brain development and function (30).

Compared with sAPPα, little is known about the putative physiological roles of other cleavage products from the non-amyloidogenic and amyloidogenic pathways. However, it has been proposed that Aβ may regulate synaptic activity, although controversial results have been reported on its beneficial versus deleterious effects (31, 32). In addition, Aβ may be involved in the control of cholesterol transport (33) and lipid homeostasis (34). For instance, direct activation of sphingomyelinase and inhibition of hydroxymethylglutaryl-CoA reductase (HMGR) by Aβ1–42 and Aβ1–40 have been demonstrated (35). The question of the physiological role of Aβ remains open, and further studies are clearly needed in this field.

The retina is a highly specialized neurosensory tissue, which lines the back of the eye. It is an integral part of the brain comprising six different types of neuronal cells and two types of macroglia cells: retinal Müller glial cells and astrocytes. Retinal and central nervous system (CNS) neurons are derived from common progenitors (36). Differentiated retinal neurons are organized into a well-defined laminar structure and are distributed into three cell and two synaptic layers. The outer segment of the retina is populated by two different types of photoreceptors: cones and rods, which are able to detect light and form the outer nuclear layer (ONL). The detected light signal is transmitted to the cells located at the inner nuclear layer (INL), mainly the bipolar cells followed by retinal ganglion cells (RGCs), either directly or indirectly via type II amacrine cells. The latter, together with horizontal cells, modulate glutamatergic neurotransmission along the main synaptic axis comprising photoreceptors, bipolar, and ganglion cells. The principal function of the INL cells is to integrate and regulate the signal input. The RGC axons converge into the optic nerve fibers, which convey the signal to the visual cortex (37).

To date, the physiological roles of APP in the retina have not been extensively investigated, although a consensus has been met about its expression by retinal pigmented epithelial (RPE) cells in the healthy retina (38). The role of APP in the development of the mouse retina has been recognized such that APP is required for the full differentiation of the AII subtype of amacrine cells. Similar to its role in the brain, APP may be implicated in retinal synaptogenesis. Indeed, APP participates in the developmental determination of the inner plexiform layer (IPL), where amacrine cells synapse to bipolar and ganglion cells (39). Concerning the physiological role of APP in adult mice, it has been shown that APP regulates inner retinal layer function. Indeed, APP-KO mice display alterations in the rod and cone pathways. However, these mice do not present any major deficits in visual function; therefore, APP is not likely a required factor (40). Among all retinal neurons, at least in the rabbit, ganglion cells are the sole cells able to synthesize and express APP on their plasma membrane in the absence of any pathological insult (41). In the human retina, APP expression is age-dependent and was revealed in RGC neurons and the RNFL (42).

Concerning Aβ, there is no published data on its putative physiological role in the retina. Of interest, the expression of BACE1 has been recently reported in the blood–brain barrier endothelial cells of mouse, bovine, and human origin, thus suggesting putative local production of Aβ in cerebral blood vessels (43). It remains unknown whether retinal vessel endothelial cells display analogous BACE1 expression. By contrast, BACE1 expression has been reported in the plexiform layer of the rat retina pointing to its synaptic localization (44).

The other parts of the eye have been much less studied in terms of the expression and function of APP and its cleavage products. However, both APP and the proteolytic enzymes involved in its cleavage were found to be expressed in some other eye compartments. For instance, APP and the secretases involved in its processing were identified in the lens (45). Similarly, Aβ was identified both in the lens (46) and in the vitreous fluid (47).

Different terms have been associated with the pathological accumulation of Aβ, with amyloidosis historically being used first. Amyloidosis is a broad term designating a metabolic disease characterized by the extracellular accumulation of globular or natively unfolded or misfolded amyloidogenic polypeptides. Amyloidogenic polypeptides contain a high proportion of β-sheets and have a great propensity to aggregate into highly organized and kinetically stable amyloid fibrils, amorphous aggregates, or oligomers. To date, more than 20 precursor proteins of fibrils (including APP) have been identified in systemic and localized amyloidosis (3). A remarkable property of these fibrils is that, independent of the type of the precursor protein, they are all 80–100Å in width. Furthermore, these fibrils organize in a tridimensional β-pleated sheet conformation with the direction of the polypeptide backbone perpendicular to the fibril axis (cross-beta structure). Another remarkable characteristic of amyloidogenic peptides and derived aggregates is their affinity for the Congo red stain (48). The Aβ-related amyloidopathies consist of increased intra- and/or extracellular accumulation of Aβ and deposition of Aβ in the form of insoluble material, such as amyloid plaques or drusens. Several disorders are associated with amyloidopathies, and most of them are neurodegenerative diseases (e.g., AD, PD, polyglutamine diseases, prion disorders, and AMD).

Amyloid-beta is produced via the amyloidogenic pathway of APP processing. However, the mechanisms by which this pathway may take over the non-amyloidogenic pathway are poorly understood, especially considering that both pathways coexist in physiological conditions (49). Many genetic and epigenetic factors may be involved, but the evidence points to an increase in the ratio of β- over α-secretase activity as a trigger. This change in the subtle balance between secretase activities in physiological conditions might be associated with the positive control of β-secretase activity by its substrate APP and directly related to APP overexpression and subsequent increase in Aβ production (50). Over the course of normal aging, Aβ is deposited subretinally in the mouse and human retina (51). With age, Aβ accumulates at the interface of the RPE and the photoreceptor outer segment tips. This finding is consistent with increased Aβ1–42 secretion by aged human RPE cells (52). As Aβ accumulates subretinally, microglial cells in normal aged mice become bloated with cellular debris and Aβ (51). The accumulation of Aβ in the subretinal space might contribute to the 23–30% reduction in photoreceptors that occurs over human lifetimes (53).

An increase in Aβ production above normal physiological levels yields cytotoxicity. Among most common Aβ species (i.e., 1–40 and 1–42 amino acid-containing isoforms), Aβ1–42 is considered the most neurotoxic as it is more prone to oligomerization (54). The amyloid aggregation pathway is still poorly understood and several intermediates are likely involved. Small soluble Aβ monomers can interact to form Aβ oligomers in the extracellular space. Aβ oligomers aggregate to form larger fibrils, which in turn aggregate to form extracellular plaques. The mechanisms of Aβ toxicity are still unclear, and different hypotheses have been proposed. According to the original “amyloid-β cascade hypothesis,” insoluble amyloid fibrils are the main molecular culprit underlying toxicity (55). More recently, this hypothesis has been revised to the “oligomeric amyloid-β hypothesis” (56). It is currently believed that the most toxic intermediates are small oligomers (with degree of polymerization lower than 10), also known as amyloid-β diffusible ligands (ADDL) or protofibrils. The latter have a bigger diffusivity and a larger surface-to-volume ratio that leads to the exposure of hydrophobic patches (57). However, it is not yet clear which oligomeric species is “the most” toxic since dimers/trimers (58), tetramers (59), and duodecamers such as Aβ*56 (60) have all been considered as plausible candidates depending on the paradigm (in vivo, in vitro) or species (murine, human) studied.

Soluble Aβ oligomers, although they are certainly not involved in all the aspects of AD, are still regarded as key initial triggers of pathogenesis (61). The bioactive pool of soluble Aβ comprises two fractions: the first is generated in the endosomal compartment and secreted into the extracellular space by exocytosis and the second is intracellular and has been found in both AD patients and animal models of the disease (62, 63). Cellular mechanisms by which soluble oligomers exert neurotoxic effects are multifaceted, involving synaptotoxicity and mitochondrial dysfunction likely related to oxidative stress and metabolic impairment. Insoluble Aβ aggregates also contribute to Aβ toxicity either directly through the release of soluble oligomers (64) or indirectly via adaptive cellular responses, such as glial and endothelial activation, which can yield neuroinflammation (65) and Aβ-related angiopathy (66), respectively.

Accumulation and aggregation of Aβ is a common denominator of a number of neurodegenerative diseases. Some of them primarily affect the eye/retina (AMD, glaucoma), while others display more specific cerebral manifestations, such as AD and PD. However, evidence is accumulating in support of retinal alterations that may reflect the cerebral neurodegeneration seen in AD and PD patients.

Based on the evidence discussed in this review, it is increasingly clear that, at least in the case of Aβ-amyloidosis, the deleterious effects that Aβ exerts on both cerebral and retinal neurons are very similar. These similarities concern alterations at both the cellular and molecular levels, such as cytokine induction and mitochondrial failure, regardless of the particular disease. Furthermore, Aβ-related alterations, such as oxidative stress, microvasculature abnormalities, and neuroinflammation, are more related to amyloidosis than to the pathological context specific to each disorder (e.g., the different composition of Aβ plaques and drusen in AD and AMD).

Amyloid-beta may therefore be an attractive common target for immunotherapy in both AMD and AD. Encouraging results were obtained after administration of anti-Aβ antibodies in mouse models of AMD (211) and AD (212) that motivated human clinical trials, in spite of some secondary effects. Although the first-generation of Aβ vaccines in AD was interrupted because of severe cerebral hemorrhage (213), new molecules are currently in clinical trials. In particular, GSK933776 was effective in both AMD phase II (214) and AD phase I (215) trials. These clinical data further point to common mechanisms in AD and AMD. Consistently, treatment with an anti-Aβ antibody in a mouse model of AMD yielded a decrease in Aβ deposits both in the retina and the brain (211).

At this stage, many challenges remain for the future. For example, it is of utmost importance to determine whether a coincident oligopathy, such as the PD-associated α-synuclein amyloidosis, may affect Aβ-amyloidosis output in the retina. Understanding whether these two amyloidoses yield additive or synergistic pathological alterations may be very helpful for designing new and more global therapeutic approaches for all relevant diseases.

It is now largely recognized that neurodegenerative alterations in the retina reflect those occurring in the brain, thus raising the hope of using the retina as a source of diagnostic biomarkers for cerebral neurodegeneration. The retina has attracted much interest since, when compared with the brain, it displays the advantage of being relatively less complex structurally and more accessible to non-invasive exploration. Indeed, it may 1 day be possible to use the retina as a proxy to diagnose early neurodegenerative alterations in the brain to target them before neurodegeneration becomes irreversible.

AM wrote the first draft of the manuscript, managed the references, and prepared the Figure 2. VD prepared the Figure 1 and brought constructive changes to the text of the manuscript. CC significantly reviewed the text and worked on references indexing. FM made the major modifications in the course of successive reviewing. SK conceived and supervised the preparation of the review.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AM and handling editor declared their shared affiliation, and the handling editor states that the process nevertheless met the standards of a fair and objective review.