Traditionally associated with neurodegenerative disorders like Alzheimer’s disease (AD), the abnormal accumulation of proteins such as tau and amyloid-β in specific brain regions leads to a range of distinct clinical syndromes, each characterized by a unique pattern of neurogeographical involvement. This concept of “neurogeography” is crucial in understanding the specific clinical manifestations of each disorder. AD is the most common neurodegenerative dementia, representing over 50% of all causes of dementia. The pathological hallmarks of AD include the presence of senile plaques, neurofibrillary tangles, neuronal cell loss, reactive gliosis and, in some cases, cerebrovascular amyloid deposits. Senile plaques are generated by deposition and accumulation of the beta-amyloid (Aβ) peptide (Ae and Clark, 2022).

Age-related macular degeneration (AMD) is a progressive decline of retinal pigmented epithelium (RPE) normal function, representing the leading cause of low vision up to central irreversible blindness in industrialized countries (Christoforidis et al., 2011). The pooled global prevalences of early and late-stage disease in adult populations are 8.01% and 0.37%, respectively (Wong et al., 2014). Numerous modifiable and non-modifiable AMD risk factors have been identified, with smoking being the primary modifiable risk factor (Heesterbeek et al., 2020). The earliest visible clinical sign of RPE impairment is the appearance of drusen. Several clinical and pathological characteristics of AD and AMD are similar, indicating overlap in pathology. The phenotypic parallelism between those entities is strongly highlighted by experimental evidence that the Aβ peptide – the main biochemical component of extracellular senile plaques in AD – is also found into ocular drusen in AMD. Moreover, common features include inflammation, hyperphosphorylated tau presence, oxidative stress, and several risk factors such as age, obesity, atherosclerosis, and hypertension. Eventually, in both AMD eyes and AD brains, there are changes in the key protein quality control mechanisms that repair damage caused by oxidative stress. These mechanisms include the autophagic, lysosomal, and proteasomal signal transduction pathways (Kaarniranta et al., 2011). This imbalance in clearance systems likely causes an intracellular buildup in misfolded/damaged proteins, including Aβ and phospho-tau (Ohno-Matsui, 2011), which ends up in the formation of detrimental insoluble aggregates in the brain and in the eye (Bruni et al., 2020). In this review, we will explore the potential parallels between the neurodegenerative processes in diseases like Alzheimer’s and the retinal changes observed in AMD. By examining the latest research and evidence, we aim to provide a comprehensive overview of AMD as a possible proteinopathy, contributing to the broader understanding of these complex diseases.

The human retina embryologically derives from the diencephalon and shares many features with brain tissue, to the extent that it is reasonably regarded as an extension of the central nervous system. Embryonically, nervous tissue originates from the ectoderm, the outermost primitive germ layer of the embryo, which differentiates into the superficial ectoderm, the neural crest and the neural tube. The neural crest and the neural tube give rise to the neural plate, forming various components of the nervous systems, including the central nervous system, optic nerve, and retina. Around the 18th day of life, an outpouching known as the primary optic vesicle emerges on the neuroectodermal wall of the embryonic forebrain (Darnell and Gilbert, 2016). This structure transforms, evolving into the secondary optic vesicle or optic cup. The optic cup, formed from an infolding of the neuroectodermal wall, consists of two layers, an outer one contributing to the pigmented layer of the retina and an inner one giving rise to the nervous layer, including light-sensing rods and cones. This developmental process concludes by the seventh month, enabling the eye’s sensitivity to light, while the differentiation of the fovea centralis occurs 4 months after birth. Overall, the resemblance in physiological characteristics between the brain and the retina underscores their shared evolutionary origins and interconnected roles in processing sensory information to support various nervous system functions (Mahabadi and Al Khalili, 2023). As neuropathological changes in retinal neurons might mirror brain pathology, a growing hypothesis has suggested its potential role as a “window to the brain” in recent years (Chiquita et al., 2019; Passaro et al., 2023). It engages in intricate processing of visual stimuli before their transmission to the brain. Simultaneously, it processes various facets of the visual environment via parallel pathways directly linked to the occipital cortex, commencing from the optic nerves. Feedback mechanisms between the retina and the brain allow dynamic adjustments in visual processing based on changing environmental conditions. The retina is not merely a passive sensor but actively participates in the neural network responsible for vision. The close integration of the retina with the brain highlights the sophisticated nature of the visual system. In summary, the retina shares structural, developmental, and functional characteristics with the central nervous system, establishing it as an extension of the brain (De Moraes, 2013).

Growing evidence has shown that brain and retinal pathologies share common physio-pathological pathways and clinical features (Trick et al., 1989; Parisi et al., 2001). Several reports have demonstrated the existence of functional changes in the retina of AD patients (Katz et al., 1989; Trick et al., 1989; Parisi et al., 2001; Krasodomska et al., 2010). Those studies, mainly based on pattern electroretinogram (PERG) recordings, reported a decrease in the amplitude and a delay in the latency of the RGCs response, without changes in the visual acuity, trying to establish possible correlations between brain and retina (Trick et al., 1989). Chiquita et al. (2019) reported a decrease of the PERG amplitude in AD patients that is consistent with a delay in the latency of visual evoked potentials (PEV), concluding that the retina could serve as a gateway to further investigate brain pathologies. These conclusions align with the systematic metanalysis conducted by Ge et al. (2021), in which they even state that structural, vascular, and electrophysiological retinal biomarkers hold great potential for the diagnosis, prognosis, and risk assessment of AD and mild cognitive impairment (MCI). They indeed concluded that as thinner retina and choroid, reduced complexity of vessels, and reduced blood flow were found in the MCI stage, retinal biomarkers have great potential utility for early neurodegenerative disease detection (Ge et al., 2021). All these findings highlight the close physiopathological connection between these two systems, clearly defining the importance of examining retinal anatomy and physiopathology to better understand neurodegenerative pathologies and vice versa. They, therefore, plainly indicate the need for further investigation to better understand their significance and, thus, the therapeutic implications. Is it possible to evaluate a synergistic pharmacological approach in aging pathology that has a real impact on processes common to both?

Age-related macular degeneration, a gradually progressive neurodegenerative retinal condition, has swiftly emerged as the primary cause of vision impairment among the elderly in developed countries, affecting the macular region of the retina (Katz et al., 1989; Trick et al., 1989). The AMD etiology is known to be multifactorial, in addition to a strong genetic component, environmental risk factors such as smoking, obesity, arteriosclerosis, hypertension, and hypercholesterolemia may predispose to AMD (Klein et al., 2004; Katta et al., 2009). AMD is categorized into two types: dry and wet forms. Dry AMD, also known as non-exudative AMD, is marked by the presence of drusen, which are lipid-rich extracellular deposits. In advanced stages, non-exudative AMD, referred to as called geographic atrophy (GA), leads to a gradual deterioration of the RPE and subsequent loss of photoreceptors. On the other hand, wet AMD, or exudative AMD, is characterized by choroidal neovascularization (Xu et al., 2018). The features and pattern of amyloid deposition in drusen and sub-RPE deposits have been investigated in subsequent years, alongside efforts to thoroughly define the proteome of these deposits. Dentchev et al. (2003) characterized the distribution of beta-amyloid in drusen from AMD and normal post-mortem human retinas, finding drusen containing Aβ just in AMD patients’ eyes. Moreover, they found that the number of Aβ positive drusen correlated with the stage of the disease and the coexistence of GA (Dentchev et al., 2003). It is noteworthy that drusen share common molecular constituents with AD amyloid plaques, such as Aβ, vitronectin, apolipoprotein E complement components and inflammatory mediators (Isas et al., 2010). Finally, it is well known that aging causes the decrease of hydraulic conductivity in Bruch’s membrane and changes in lipid content in the retina (Miller-Thomas et al., 2016). Parallel to age, chronic oxidative stress can induce RPE senescence. The synthesis of beta-amyloid is most likely both the cause and the result of these occurrences taken together. Thus, the release of proteases and proinflammatory cytokines results in an irreversible positive feedback process (Feng et al., 2023). According to recent research, inflammation and chronic oxidative stress are strongly linked to AMD and AD pathogenesis (Beatty et al., 2000; Kaarniranta et al., 2011). Complement activation serves as a central mechanism in both AMD and AD pathology models. However, while the classical pathway is thought to play a major role in AD, the alternative pathway is predominantly involved in AMD (McGeer et al., 2005).

Tauopathies and retinal degeneration share common physio-pathological pathways, a notion substantiated by robust evidence in the literature (Figure 1; Biscetti et al., 2017; Xu et al., 2018; Wang and Mao, 2021).

According to the findings shown above, oxidative stress is a major factor in AMD pathogenesis, inducing a range of DNA lesions, with 8-oxo-7,8-dihydroguanine (8-oxoG) functioning as a marker of oxidative DNA damage and a prominent mutagenic mediator of oxidative stress (Kushwah et al., 2023). Previous studies discovered that lymphocytes from AMD patients have more endogenous DNA damage than lymphocytes from healthy persons (Blasiak et al., 2013a).

The RPE cells can undergo oxidative stress-induced senescence despite remaining dormant. They proliferate (Glotin et al., 2008; Marazita et al., 2016). In fact, several studies that used human RPE-derived ARPE-19 cells that proliferate in vitro showed how oxidative stress causes cell senescence. Cellular senescence is caused by persistent DNA damage response (DDR) orchestrated by the serine/threonine-protein kinases ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related), which are the major cell sensors of DNA damage (Pezone et al., 2023). On the other hand, oxidative damage restricts the replication and transcription of mitochondrial DNA (mtDNA), diminishing mitochondrial function and leading to a rise in ROS production, further mtDNA damage, and senescence (Correia-Melo and Passos, 2015; Perillo et al., 2020).

DNA damage response is a complicated signal-transduction process that detects DNA lesions (SSBs and DSBs) and organizes brief cell-cycle arrest, DNA repair, autophagy, apoptosis, or permanent growth arrest (senescence) depending on their severity (De Zio et al., 2013; Feringa et al., 2018; Lanz et al., 2019; Kargapolova et al., 2021). It depends on activating of sensor kinases (ATM, ATR, and DNA-dependent protein kinase). If DNA damage continues, the senescence phenotype emerges gradually through the induction of checkpoint proteins such as p53, p21, and p16, which induce cell-cycle arrest and senescence (Medzhitov, 2021). Surprisingly, this anti-proliferative response (induction of p16 and p21) is also present in non-replicating postmitotic cells and stem cells following DNA damage to maintain cell survival (Yosef et al., 2017; Kumari and Jat, 2021; Von Zglinicki et al., 2021).

Senescence is induced by a persistent DNA damage response that reduces the NAD+ pool and favors the senescence-associated secretory phenotype (SASP) and mitochondrial malfunction. Although some inconsistent interpretations imply that SASP has either favorable or negative effects on the course of age-related illnesses or neoplasia, the relationship between SASP and DDR is well established (Gorgoulis et al., 2019; Pezone et al., 2023). DDR-induced inflammatory phenotypes, which have defense and messaging roles in complex cell populations, might, on the other hand, result in a prolonged inflammatory milieu that promotes the accumulation of DNA mutations and genomic instability. Persistent inflammation and DDR are the molecular processes that underpin genomic and chromosomal instability, culminating in the reactivation of repressed genes in aged neurons (Morano et al., 2014; Russo et al., 2016, 2021; Tijhuis et al., 2019). DNA methylation and PRC complex binding loss or increase are found in aged cells. Mechanistically, homology-directed DSB repair leads to strand-specific editing of local methylation (Allen et al., 2017; Tijhuis et al., 2019; Tramontano et al., 2020) resulting in cells with hypermethylated and hypomethylated DNA (Sandovici et al., 2006; O’Hagan et al., 2008) and global transcriptional reprogramming (Pezone et al., 2017; Xiao et al., 2019; Improda et al., 2023).

DNA damage response processes work to repair DNA damage. However, if a cell’s DNA is seriously damaged, the cell will either go into dormancy or will undergo programmed cell death. Autophagy affects a cell’s destiny following DNA damage by acting as a prosurvival process as well as a kind of cell death. According to some research, autophagy delays DNA damage-induced apoptosis by supplying energy for DNA repair (Demirbağ-Sarikaya et al., 2021). By removing harmful aggregates that might be a source of ROS, autophagy often supports DDR and indirectly reduces DNA damage (Blasiak et al., 2017).

Numerous DDR proteins have a role in controlling autophagy. To repair DNA single-strand breaks, PARP1 catalyzes the polyribosylation of nuclear proteins by converting NAD+ into polyADP-ribose polymers. As a result, the energetic imbalance that triggers autophagy through the AMPK pathway, recycling metabolic precursors for ATP and providing energy for DDR. This results in NAD+ depletion and ATP use (Muñoz-Gámez et al., 2009). As model organisms age, autophagy often decreases, leading to a buildup of cellular waste and browning of the cells (Rubinsztein et al., 2011).

Retinal pigmented epithelium cell senescence may also be directly associated with mitochondrial malfunction. Dysfunctional mitochondria lead to higher amounts of ROS, mtDNA damage, and impaired metabolic performance. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma (PGC-1α) is essential for mitochondrial biogenesis and oxidative metabolism. Recently DNA sequence variants in PPARGC1A gene coding for PGC-1α were reported to be associated with neovascular AMD and AMD-associated loci (Gurubaran et al., 2023). Moreover, PGC-1α has been found to influence lysosomal activity in neurons and RPE cells, increasing autophagy flux and eliminating cell damage (Tsunemi et al., 2012). In same study, it was also shown that PGC-1 defective animals exhibited several RPE abnormalities, which were connected with their accelerated senescence (Kaarniranta et al., 2018).

In summary, irreversible pathogenic processes including RPE loss and inflammation may be aided by or preceded by RPE senescence in the retina, which is peculiar to AMD. Senescent RPE cells may become excessively harmed and dysfunctional due to SASP overexpression.

The neural retina, being a component of the brain, endures the same changes as the aging brain. The brain is prone to aging, which appears as changes in its structure and cognitive processes (Wrigglesworth et al., 2022). In AMD and AD pathogeneses share several risk factors such as age, obesity, atherosclerosis, and hypertension (Kaarniranta et al., 2011) but share also several mechanisms, such as inflammation, tau hyperphosphorylation, oxidative stress, drusen and alternative complement cascade activation (Meri and Haapasalo, 2020). Aβ plaques, a hallmark of AD, can then be present in AMD drusen and may enhance complement activation by blocking complement factor I (CFI) (Mirzaei et al., 2020).

Alzheimer’s disease brains are distinguished by neuronal death and the formation of plaques containing A fibrils. Nonetheless, several studies imply that soluble Aβ species may be implicated in pathogenic AD episodes (Miller-Thomas et al., 2016). Drusen, extracellular deposits formed by the aged retina, are similar to senile plaques found in the aging brain.

In cell cultures, experimental animals, and human post-mortem eyes, experimental exposure of the neural retina, RPE, and choroid to Aβ resulted in local retinal inflammation. In rat retinas (Lynn et al., 2017; Pezone et al., 2023), Aβ was shown to accumulate in lysosomes, affecting RPE function and producing an AMD-like phenotype (Lynn et al., 2017). These effects might be linked to lysosomal clearance impairment caused by aging and AMD (Kaarniranta et al., 2018).

Beta-amyloid has been shown to promote RPE cell senescence as well as to disrupt mitochondrial metabolism (Muraleva et al., 2019). Both effects have been identified as involved in the etiology of AMD (Blasiak, 2020).

Senescent cells’ production of SASP-derived substances may cause low-grade inflammation, which is critical in developing AMD and other neurological disorders (Carreno et al., 2021).

Senescent alterations in the expression pattern of several proteins may result in microglia activation and structural abnormalities associated with AMD (Indaram et al., 2015).

Al-Hussaini et al. (2008) suggested that RPE cells in the central retina stay quiescent due to space restrictions and contact with neuroretina, and when wounded, they can be replaced by their developing counterparts at the RPE periphery in an endogenous compensatory mechanism. This endogenous regeneration mechanism is increased in pathogenic circumstances, which may deteriorate with age (Xia et al., 2011). If RPE cells are prone to senescence, it can lead to the inability of peripheral RPE cells to rescue their central RPE counterparts, resulting in a significant loss of RPE cells in clinically evident AMD. This pathway may malfunction and lead to AMD if the majority of the macular peripheral RPE cells are impacted by senescence. Senescent RPE will be the disease’s cause, negatively impacting surrounding tissue through SASP (Figure 2).

In conclusion, oxidative damage, Aβ deposits and phosphorylated tau may play an important role in the pathogenesis of AMD and serve as a reliable measure of real retina aging with potential applications in diagnosis and treatment. These factors may be connected to oxidative stress, decreased mitochondrial and lysosomal function, inflammation, and particular complement system genotypes, among other consistent aspects of AMD development. Aβ deposits may be seen in both dry and wet AMD, and several pathways may highlight the negative consequences of Aβ deposition in AMD pathogenesis (Kaarniranta et al., 2020). Systemic and ocular levels of oxidative damage are currently evaluated as diagnostic and/or even predictive biomarkers of both AMD and tauopathies (Blasiak et al., 2013b).

Most current treatments temporarily prevent tissue degradation by reducing inflammation or complement dysregulation using anti-inflammatory, antioxidant, or antiangiogenic medications. However, based on similarities between AMD and tauopathies, an increasing number of opportunities are emerging with the administration of specific senolytics targeting aging cells (Chung and Kim, 2022) as a common therapeutic agent and neuroprotective strategy for AMD and tauopathies. Currently, a pilot clinical trial has been made to evaluate the effectiveness of senolytic therapy in modulating the progression of AD, which drives cellular senescence in the brain (Chung and Kim, 2022).

We believe that this observation will aid many other degenerative eye disorders (such as ocular scarring pemphigoid, OCP, or glaucoma) (Passaro et al., 2023) by elucidating the shared pathophysiology (DNA damage and inflammation associated with senescence).

For this review, an extensive exploration of literature was conducted from October 2023 to February 2024, utilizing the PubMed, Scopus, and Cochrane databases. No time limits were set in the searches. Our search methodology comprised a blend of keywords aimed at encompassing pertinent studies, such as “neurodegeneration,” “retina,” “maculopathy,” “AMD,” “tau,” “tauopathy,” and combinations of them. The articles identified underwent meticulous review and analysis, synthesizing a thorough understanding of what is known in this domain of study. Figures are made in BioRender.com.

MR: Conceptualization, Writing – review & editing. APe: Conceptualization, Supervision, Writing – review & editing. GQ: Investigation, Writing – review & editing. GA: Writing – review & editing. ML: Writing – review & editing. MP: Writing – review & editing. APo: Supervision, Writing – review & editing. CC: Project administration, Supervision, Writing – review & editing.