PMC:7523471 / 25090-35501 JSONTXT

{"project":"TEST0","denotations":[{"id":"33041751-209-217-816363","span":{"begin":251,"end":255},"obj":"[\"19184068\"]"},{"id":"33041751-231-239-816364","span":{"begin":273,"end":277},"obj":"[\"28973551\"]"},{"id":"33041751-227-235-816365","span":{"begin":296,"end":300},"obj":"[\"31157827\"]"},{"id":"33041751-147-155-816366","span":{"begin":450,"end":454},"obj":"[\"7822152\"]"},{"id":"33041751-231-239-816367","span":{"begin":698,"end":702},"obj":"[\"7822152\"]"},{"id":"33041751-232-240-816368","span":{"begin":718,"end":722},"obj":"[\"21157377\"]"},{"id":"33041751-158-166-816369","span":{"begin":883,"end":887},"obj":"[\"7822152\"]"},{"id":"33041751-178-186-816370","span":{"begin":903,"end":907},"obj":"[\"21157377\"]"},{"id":"33041751-232-240-816371","span":{"begin":1175,"end":1179},"obj":"[\"3736630\"]"},{"id":"33041751-228-236-816372","span":{"begin":1196,"end":1200},"obj":"[\"2819446\"]"},{"id":"33041751-142-150-816373","span":{"begin":1345,"end":1349},"obj":"[\"23714377\"]"},{"id":"33041751-165-173-816374","span":{"begin":1368,"end":1372},"obj":"[\"28379416\"]"},{"id":"33041751-227-235-816375","span":{"begin":1560,"end":1564},"obj":"[\"23300938\"]"},{"id":"33041751-87-95-816376","span":{"begin":1654,"end":1658},"obj":"[\"30593285\"]"},{"id":"33041751-110-118-816377","span":{"begin":1677,"end":1681},"obj":"[\"31551688\"]"},{"id":"33041751-234-242-816378","span":{"begin":2048,"end":2052},"obj":"[\"23300938\"]"},{"id":"33041751-226-234-816379","span":{"begin":2071,"end":2075},"obj":"[\"30593285\"]"},{"id":"33041751-189-197-816381","span":{"begin":2533,"end":2537},"obj":"[\"30593285\"]"},{"id":"33041751-158-166-816382","span":{"begin":3021,"end":3025},"obj":"[\"30593285\"]"},{"id":"33041751-63-71-816383","span":{"begin":3783,"end":3787},"obj":"[\"23300938\"]"},{"id":"33041751-66-74-816384","span":{"begin":3856,"end":3860},"obj":"[\"28814675\"]"},{"id":"33041751-233-241-816385","span":{"begin":4188,"end":4192},"obj":"[\"19184068\"]"},{"id":"33041751-198-206-816386","span":{"begin":4393,"end":4397},"obj":"[\"23300938\"]"},{"id":"33041751-221-229-816387","span":{"begin":4416,"end":4420},"obj":"[\"30593285\"]"},{"id":"33041751-162-170-816388","span":{"begin":4585,"end":4589},"obj":"[\"28814675\"]"},{"id":"33041751-112-120-816389","span":{"begin":4861,"end":4865},"obj":"[\"23300938\"]"},{"id":"33041751-217-225-816390","span":{"begin":4966,"end":4970},"obj":"[\"30593285\"]"},{"id":"33041751-161-169-816391","span":{"begin":5134,"end":5138},"obj":"[\"30593285\"]"},{"id":"33041751-184-192-816392","span":{"begin":5157,"end":5161},"obj":"[\"31551688\"]"},{"id":"33041751-233-241-816393","span":{"begin":5908,"end":5912},"obj":"[\"16085339\"]"},{"id":"33041751-231-239-816394","span":{"begin":5928,"end":5932},"obj":"[\"19142572\"]"},{"id":"33041751-235-243-816395","span":{"begin":6389,"end":6393},"obj":"[\"25482990\"]"},{"id":"33041751-60-68-816396","span":{"begin":6456,"end":6460},"obj":"[\"30593285\"]"},{"id":"33041751-83-91-816397","span":{"begin":6479,"end":6483},"obj":"[\"31551688\"]"},{"id":"33041751-147-155-816398","span":{"begin":6543,"end":6547},"obj":"[\"28814675\"]"},{"id":"33041751-192-200-816400","span":{"begin":6588,"end":6592},"obj":"[\"31551688\"]"},{"id":"33041751-230-238-816401","span":{"begin":7015,"end":7019},"obj":"[\"9920498\"]"},{"id":"33041751-232-240-816402","span":{"begin":7036,"end":7040},"obj":"[\"12202516\"]"},{"id":"33041751-235-243-816403","span":{"begin":7056,"end":7060},"obj":"[\"16464969\"]"},{"id":"33041751-235-243-816404","span":{"begin":7074,"end":7078},"obj":"[\"17684098\"]"},{"id":"33041751-226-234-816405","span":{"begin":7087,"end":7091},"obj":"[\"20709058\"]"},{"id":"33041751-203-211-816406","span":{"begin":7297,"end":7301},"obj":"[\"16085339\"]"},{"id":"33041751-223-231-816407","span":{"begin":7317,"end":7321},"obj":"[\"18219347\"]"},{"id":"33041751-81-89-816408","span":{"begin":7592,"end":7596},"obj":"[\"26733792\"]"},{"id":"33041751-228-236-816409","span":{"begin":7949,"end":7953},"obj":"[\"20410146\"]"},{"id":"33041751-230-238-816410","span":{"begin":7969,"end":7973},"obj":"[\"21157377\"]"},{"id":"33041751-226-234-816411","span":{"begin":7987,"end":7991},"obj":"[\"28887373\"]"},{"id":"33041751-232-240-816412","span":{"begin":8007,"end":8011},"obj":"[\"28208185\"]"},{"id":"33041751-229-237-816413","span":{"begin":8031,"end":8035},"obj":"[\"29459346\"]"},{"id":"33041751-230-238-816414","span":{"begin":8049,"end":8053},"obj":"[\"31019447\"]"},{"id":"33041751-208-216-816415","span":{"begin":8490,"end":8494},"obj":"[\"7822152\"]"},{"id":"33041751-234-242-816416","span":{"begin":8756,"end":8760},"obj":"[\"21157377\"]"}],"text":"Retinal Tauopathy in Alzheimer’s Patients\nAnother key characteristic sign of AD neuropathology that strongly reflects neuronal injury and cognitive decline is abnormal tau, specifically hyperphosphorylated tau and its inclusion in NFTs (Iqbal et al., 2009; Buckley et al., 2017; Hanseeuw et al., 2019). The physiological distribution pattern of total non-phosphorylated tau expression in the human retina was first described in 1995 (Loffler et al., 1995). According to this report and subsequent studies, tau is predominantly expressed in the inner retinal layers, most intensely along three distinct bands in the IPL, more diffusely in the OPL and somatodendritically in the INL (Loffler et al., 1995; Leger et al., 2011). Tau is also localized, albeit weakly, in other inner retinal layers such as the GCL and NFL as well as in photoreceptors of the human retina (Loffler et al., 1995; Leger et al., 2011).\nInitial post-mortem examinations of late-stage AD retinas did not reveal neurofibrillary inclusions, neuritic plaques or amyloid angiopathy, despite histological observations of GCL degeneration, reduced NFL thickness and optic nerve axonal atrophy (Hinton et al., 1986; Blanks et al., 1989). While a limited number of studies have been unable to histopathologically detect abnormal tau accumulation in retinas of patients (Ho et al., 2014; Williams et al., 2017), the first evidence of disease-associated tau hyperphosphorylation in post-mortem retinas of confirmed AD cases was reported by Schön and colleagues in 2012 (Figures 4A,B; Schön et al., 2012). Results from this study were corroborated thereafter by other groups (den Haan et al., 2018; Grimaldi et al., 2019). Different pTau species, recognized by phosphorylation site-specific antibodies such as AT8 (pSer202, pThr205), AT100 (pThr212 and pSer214), and AT270 (pThr181), were primarily found in the inner retinal layers, particularly the plexiform layers, INL, and GCL of AD patients, thus closely mirroring the physiological expression pattern of normal tau (Schön et al., 2012; den Haan et al., 2018). Interestingly, a recent independent report on a quantitative histomorphometric analysis of post-mortem tissue revealed that these particular retinal layers undergo significant pathological atrophy in AD compared to non-demented control cases (Asanad et al., 2019b). Geometric analysis of postmortem retinal tissue from 6 control cases and 6 AD patients showed more intense AT8-immunoreactivity in superior than in medial retinal regions (den Haan et al., 2018). Qualitative observations from the same study also showed a positive gradient away from the optic nerve and toward the periphery. Despite the presence of pTau in all 6 AD retinas, no significant difference was found in retinal pTau area coverage between the two diagnostic groups, likely due to 2 outliers in control cases. Importantly, a novel and significant association was also found between retinal AT8 burden and cerebral amyloid plaque but not NFT severity (den Haan et al., 2018).\nFIGURE 4 Evidence of hyperphosphorylated pTau inclusions in AD retina. (A–E) Representative micrograph images of retinal cross-sections from AD patients following (A,B) immunostaining with AT8 mAb against phospho-tau (Ser202, Thr205), revealing intracellular pTau aggregates in both inner and outer nuclear layers (INL and ONL), and plexiform layers (IPL and OPL). Scale bars: 10 μm; (C,D) Higher magnification images of inner retina stained with Gallyas silver showing neurofibrillary tangle (NFT)-like structures in ganglion cell layer (GCL). (E) Immuofluorescence staining of AT100 mAb against phospho-tau (Thr212, Ser214) showing punctate aggregates and intracellular inclusions in INL. Images and data of panels (A,B) are adapted from Schön et al. (2012). Images and data of panels c-d are reproduced from Koronyo et al. (2017) with permission of ASCI via Copyright Clearance Center. Hyperphosphorylation of tau has been shown to drive the formation of fibrillar tau inclusions and neurofibrillary tangles, leading to disruptions in axonal transport as well as metabolic and oxidative stress, and is closely associated with neuronal death (Iqbal et al., 2009). Although several histological staining approaches have been utilized to confirm the presence of fibrillar inclusions of pTau in human AD retinas, thus far many have been unsuccessful (Schön et al., 2012; den Haan et al., 2018). To date, only one study using Gallyas silver staining detected NFT-like structures in postmortem retinas of definitive AD patients (Figures 4C,D; Koronyo et al., 2017). As mentioned above, there is an apparent gap in results obtained from different groups, possibly driven by the lack of standardized experimental procedures. For instance, the same antibodies against pTau reported to produce negative results by one group (Schön et al., 2012) detected pTau staining patterns similar to AT8-immunoreactivity in a later study (den Haan et al., 2018). Still, by utilizing AT100 antibody, two independent groups detected similar patterns of pTau in postmortem retinas from AD patients (Figure 4E; den Haan et al., 2018; Grimaldi et al., 2019). Future investigations would therefore be necessary to confirm the presence or absence of disease-associated tau conformers in the retinas of AD patients.\nMoreover, it is still unclear whether abnormal hyperphosphorylation of tau and/or formation of intracellular tangles have similar detrimental consequences in the retinas of patients as those observed in the brain. Analyses of retinal changes in AD transgenic mice support this putative association and will be discussed in the following sections. According to data from clinical studies and meta-analyses, levels of total tau and pTau in the CSF remain among the most reliable and sensitive biomarkers for both AD diagnosis and longitudinal monitoring of disease progression (Ibach et al., 2006; Welge et al., 2009; AlzBiomarker Database, 2018). Several lines of evidence indicate that CSF tau levels are significantly increased in AD patients (AlzBiomarker Database, 2018). Intriguingly, CSF total tau and pTau-181 concentrations were shown to correlate with retinal changes measured by fluorescent lifetime ophthalmoscopy, a technique suggested to detect the metabolic alterations of tissue represented by fluorescence decay of endogenous fluorophores (Jentsch et al., 2015). Nevertheless, the co-localization of pTau (den Haan et al., 2018; Grimaldi et al., 2019) and sites of neuronal loss in the retina (Koronyo et al., 2017; Asanad et al., 2019b; Grimaldi et al., 2019) are indicative of similar physiological vulnerabilities to pTau accumulation in both the retina and brain.\nRetinal disorders such as glaucoma and age-related macular degeneration (AMD) share a number of common features with AD retinal pathology including progressive deposition of protein aggregates, reactive gliosis and pro-inflammatory responses, metabolic dysfunction, oxidative stress, and retinal atrophy (Quigley, 1999; Naskar et al., 2002; Gupta et al., 2006; Guo et al., 2007; Tezel, 2011). In 2008, examination of retinal tauopathy in surgically removed tissue from human glaucoma cases revealed intense localization of AT8-positive pTau in horizontal cells residing in the OPL (Ibach et al., 2006; Gupta et al., 2008). It is hypothesized that the lateral arrangement of horizontal cell processes may predispose them to retinal stretch injury caused by glaucoma-related elevated intraocular pressure (IOP). Although no association was found between high IOP and dementia (Cesareo et al., 2015), it remains to be seen whether similar changes occur due to AD-associated ocular abnormalities. However, increased retinal pTau accumulation and atrophy following injury or due to other neurodegenerative disorders reveal the vulnerability of this neural tissue compartment to structural, functional, and neuropathological abnormalities (Green et al., 2010; Leger et al., 2011; Kim et al., 2017; Satue et al., 2017; Behbehani et al., 2018; Kim et al., 2019).\nAging remains the principal risk factor in AD and is tightly associated with several visual impairments. To date, only two studies have investigated the relationship between aging and total tau expression in the human retina. An early semi-quantitative analysis found no difference between tau immunoreactivity in post-mortem retinas from young and old healthy subjects, although age ranges were not clearly outlined (Loffler et al., 1995). Another study, examining retinas from enucleated eyes of patients with prior history of ocular disorders, reported a positive correlation between aging and total tau levels in RGCs in a subset of patients, while unable to find evidence of pTau (Leger et al., 2011). Such reports further showcase the disparity in these findings and reiterate the need for replication of these studies. Notably, the effects of aging on the abnormal accumulation of pTau in retinas of healthy individuals and/or patients also remains unexplored.\nAs it relates to tau imaging in the retina, there are currently no live imaging tools to specifically detect tau aggregates in the human retina. Preliminary results from a study that utilized spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescein (FAF) to visualize pathological tau aggregates in a cohort of PET-confirmed Alzheimer’s patients (Kayabasi, 2018) hints at the possibility of noninvasive live imaging and monitoring of neuropathological changes in the retina of MCI and AD patients; however, the specificity of the signal was not clear.\nOverall, it is apparent that investigations of retinal Aβ pathology and its relationship with cerebral amyloid plaque burden in AD patients are mounting. However, our understanding of retinal pTau accumulation and associations with brain NFT severity is much more limited. To date, only a few groups have successfully detected tau hyperphosphorylation in post-mortem human retinas from AD patients, and only one study has shown an association between retinal pTau and cerebral amyloid load in a small number of AD patients. Therefore, there is an urgent need for systematic and quantitative analyses of retinal pTau in larger cohorts as well as assessment of both the spatiotemporal and pathomechanistic properties of AD-related tau species in the retina and their relationship with brain disease and cognition."}

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The physiological distribution pattern of total non-phosphorylated tau expression in the human retina was first described in 1995 (Loffler et al., 1995). According to this report and subsequent studies, tau is predominantly expressed in the inner retinal layers, most intensely along three distinct bands in the IPL, more diffusely in the OPL and somatodendritically in the INL (Loffler et al., 1995; Leger et al., 2011). Tau is also localized, albeit weakly, in other inner retinal layers such as the GCL and NFL as well as in photoreceptors of the human retina (Loffler et al., 1995; Leger et al., 2011).\nInitial post-mortem examinations of late-stage AD retinas did not reveal neurofibrillary inclusions, neuritic plaques or amyloid angiopathy, despite histological observations of GCL degeneration, reduced NFL thickness and optic nerve axonal atrophy (Hinton et al., 1986; Blanks et al., 1989). While a limited number of studies have been unable to histopathologically detect abnormal tau accumulation in retinas of patients (Ho et al., 2014; Williams et al., 2017), the first evidence of disease-associated tau hyperphosphorylation in post-mortem retinas of confirmed AD cases was reported by Schön and colleagues in 2012 (Figures 4A,B; Schön et al., 2012). Results from this study were corroborated thereafter by other groups (den Haan et al., 2018; Grimaldi et al., 2019). Different pTau species, recognized by phosphorylation site-specific antibodies such as AT8 (pSer202, pThr205), AT100 (pThr212 and pSer214), and AT270 (pThr181), were primarily found in the inner retinal layers, particularly the plexiform layers, INL, and GCL of AD patients, thus closely mirroring the physiological expression pattern of normal tau (Schön et al., 2012; den Haan et al., 2018). Interestingly, a recent independent report on a quantitative histomorphometric analysis of post-mortem tissue revealed that these particular retinal layers undergo significant pathological atrophy in AD compared to non-demented control cases (Asanad et al., 2019b). Geometric analysis of postmortem retinal tissue from 6 control cases and 6 AD patients showed more intense AT8-immunoreactivity in superior than in medial retinal regions (den Haan et al., 2018). Qualitative observations from the same study also showed a positive gradient away from the optic nerve and toward the periphery. Despite the presence of pTau in all 6 AD retinas, no significant difference was found in retinal pTau area coverage between the two diagnostic groups, likely due to 2 outliers in control cases. Importantly, a novel and significant association was also found between retinal AT8 burden and cerebral amyloid plaque but not NFT severity (den Haan et al., 2018).\nFIGURE 4 Evidence of hyperphosphorylated pTau inclusions in AD retina. (A–E) Representative micrograph images of retinal cross-sections from AD patients following (A,B) immunostaining with AT8 mAb against phospho-tau (Ser202, Thr205), revealing intracellular pTau aggregates in both inner and outer nuclear layers (INL and ONL), and plexiform layers (IPL and OPL). Scale bars: 10 μm; (C,D) Higher magnification images of inner retina stained with Gallyas silver showing neurofibrillary tangle (NFT)-like structures in ganglion cell layer (GCL). (E) Immuofluorescence staining of AT100 mAb against phospho-tau (Thr212, Ser214) showing punctate aggregates and intracellular inclusions in INL. Images and data of panels (A,B) are adapted from Schön et al. (2012). Images and data of panels c-d are reproduced from Koronyo et al. (2017) with permission of ASCI via Copyright Clearance Center. Hyperphosphorylation of tau has been shown to drive the formation of fibrillar tau inclusions and neurofibrillary tangles, leading to disruptions in axonal transport as well as metabolic and oxidative stress, and is closely associated with neuronal death (Iqbal et al., 2009). Although several histological staining approaches have been utilized to confirm the presence of fibrillar inclusions of pTau in human AD retinas, thus far many have been unsuccessful (Schön et al., 2012; den Haan et al., 2018). To date, only one study using Gallyas silver staining detected NFT-like structures in postmortem retinas of definitive AD patients (Figures 4C,D; Koronyo et al., 2017). As mentioned above, there is an apparent gap in results obtained from different groups, possibly driven by the lack of standardized experimental procedures. For instance, the same antibodies against pTau reported to produce negative results by one group (Schön et al., 2012) detected pTau staining patterns similar to AT8-immunoreactivity in a later study (den Haan et al., 2018). Still, by utilizing AT100 antibody, two independent groups detected similar patterns of pTau in postmortem retinas from AD patients (Figure 4E; den Haan et al., 2018; Grimaldi et al., 2019). Future investigations would therefore be necessary to confirm the presence or absence of disease-associated tau conformers in the retinas of AD patients.\nMoreover, it is still unclear whether abnormal hyperphosphorylation of tau and/or formation of intracellular tangles have similar detrimental consequences in the retinas of patients as those observed in the brain. Analyses of retinal changes in AD transgenic mice support this putative association and will be discussed in the following sections. According to data from clinical studies and meta-analyses, levels of total tau and pTau in the CSF remain among the most reliable and sensitive biomarkers for both AD diagnosis and longitudinal monitoring of disease progression (Ibach et al., 2006; Welge et al., 2009; AlzBiomarker Database, 2018). Several lines of evidence indicate that CSF tau levels are significantly increased in AD patients (AlzBiomarker Database, 2018). Intriguingly, CSF total tau and pTau-181 concentrations were shown to correlate with retinal changes measured by fluorescent lifetime ophthalmoscopy, a technique suggested to detect the metabolic alterations of tissue represented by fluorescence decay of endogenous fluorophores (Jentsch et al., 2015). Nevertheless, the co-localization of pTau (den Haan et al., 2018; Grimaldi et al., 2019) and sites of neuronal loss in the retina (Koronyo et al., 2017; Asanad et al., 2019b; Grimaldi et al., 2019) are indicative of similar physiological vulnerabilities to pTau accumulation in both the retina and brain.\nRetinal disorders such as glaucoma and age-related macular degeneration (AMD) share a number of common features with AD retinal pathology including progressive deposition of protein aggregates, reactive gliosis and pro-inflammatory responses, metabolic dysfunction, oxidative stress, and retinal atrophy (Quigley, 1999; Naskar et al., 2002; Gupta et al., 2006; Guo et al., 2007; Tezel, 2011). In 2008, examination of retinal tauopathy in surgically removed tissue from human glaucoma cases revealed intense localization of AT8-positive pTau in horizontal cells residing in the OPL (Ibach et al., 2006; Gupta et al., 2008). It is hypothesized that the lateral arrangement of horizontal cell processes may predispose them to retinal stretch injury caused by glaucoma-related elevated intraocular pressure (IOP). Although no association was found between high IOP and dementia (Cesareo et al., 2015), it remains to be seen whether similar changes occur due to AD-associated ocular abnormalities. However, increased retinal pTau accumulation and atrophy following injury or due to other neurodegenerative disorders reveal the vulnerability of this neural tissue compartment to structural, functional, and neuropathological abnormalities (Green et al., 2010; Leger et al., 2011; Kim et al., 2017; Satue et al., 2017; Behbehani et al., 2018; Kim et al., 2019).\nAging remains the principal risk factor in AD and is tightly associated with several visual impairments. To date, only two studies have investigated the relationship between aging and total tau expression in the human retina. An early semi-quantitative analysis found no difference between tau immunoreactivity in post-mortem retinas from young and old healthy subjects, although age ranges were not clearly outlined (Loffler et al., 1995). Another study, examining retinas from enucleated eyes of patients with prior history of ocular disorders, reported a positive correlation between aging and total tau levels in RGCs in a subset of patients, while unable to find evidence of pTau (Leger et al., 2011). Such reports further showcase the disparity in these findings and reiterate the need for replication of these studies. Notably, the effects of aging on the abnormal accumulation of pTau in retinas of healthy individuals and/or patients also remains unexplored.\nAs it relates to tau imaging in the retina, there are currently no live imaging tools to specifically detect tau aggregates in the human retina. Preliminary results from a study that utilized spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescein (FAF) to visualize pathological tau aggregates in a cohort of PET-confirmed Alzheimer’s patients (Kayabasi, 2018) hints at the possibility of noninvasive live imaging and monitoring of neuropathological changes in the retina of MCI and AD patients; however, the specificity of the signal was not clear.\nOverall, it is apparent that investigations of retinal Aβ pathology and its relationship with cerebral amyloid plaque burden in AD patients are mounting. However, our understanding of retinal pTau accumulation and associations with brain NFT severity is much more limited. To date, only a few groups have successfully detected tau hyperphosphorylation in post-mortem human retinas from AD patients, and only one study has shown an association between retinal pTau and cerebral amyloid load in a small number of AD patients. Therefore, there is an urgent need for systematic and quantitative analyses of retinal pTau in larger cohorts as well as assessment of both the spatiotemporal and pathomechanistic properties of AD-related tau species in the retina and their relationship with brain disease and cognition."}

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The physiological distribution pattern of total non-phosphorylated tau expression in the human retina was first described in 1995 (Loffler et al., 1995). According to this report and subsequent studies, tau is predominantly expressed in the inner retinal layers, most intensely along three distinct bands in the IPL, more diffusely in the OPL and somatodendritically in the INL (Loffler et al., 1995; Leger et al., 2011). Tau is also localized, albeit weakly, in other inner retinal layers such as the GCL and NFL as well as in photoreceptors of the human retina (Loffler et al., 1995; Leger et al., 2011).\nInitial post-mortem examinations of late-stage AD retinas did not reveal neurofibrillary inclusions, neuritic plaques or amyloid angiopathy, despite histological observations of GCL degeneration, reduced NFL thickness and optic nerve axonal atrophy (Hinton et al., 1986; Blanks et al., 1989). While a limited number of studies have been unable to histopathologically detect abnormal tau accumulation in retinas of patients (Ho et al., 2014; Williams et al., 2017), the first evidence of disease-associated tau hyperphosphorylation in post-mortem retinas of confirmed AD cases was reported by Schön and colleagues in 2012 (Figures 4A,B; Schön et al., 2012). Results from this study were corroborated thereafter by other groups (den Haan et al., 2018; Grimaldi et al., 2019). Different pTau species, recognized by phosphorylation site-specific antibodies such as AT8 (pSer202, pThr205), AT100 (pThr212 and pSer214), and AT270 (pThr181), were primarily found in the inner retinal layers, particularly the plexiform layers, INL, and GCL of AD patients, thus closely mirroring the physiological expression pattern of normal tau (Schön et al., 2012; den Haan et al., 2018). Interestingly, a recent independent report on a quantitative histomorphometric analysis of post-mortem tissue revealed that these particular retinal layers undergo significant pathological atrophy in AD compared to non-demented control cases (Asanad et al., 2019b). Geometric analysis of postmortem retinal tissue from 6 control cases and 6 AD patients showed more intense AT8-immunoreactivity in superior than in medial retinal regions (den Haan et al., 2018). Qualitative observations from the same study also showed a positive gradient away from the optic nerve and toward the periphery. Despite the presence of pTau in all 6 AD retinas, no significant difference was found in retinal pTau area coverage between the two diagnostic groups, likely due to 2 outliers in control cases. Importantly, a novel and significant association was also found between retinal AT8 burden and cerebral amyloid plaque but not NFT severity (den Haan et al., 2018).\nFIGURE 4 Evidence of hyperphosphorylated pTau inclusions in AD retina. (A–E) Representative micrograph images of retinal cross-sections from AD patients following (A,B) immunostaining with AT8 mAb against phospho-tau (Ser202, Thr205), revealing intracellular pTau aggregates in both inner and outer nuclear layers (INL and ONL), and plexiform layers (IPL and OPL). Scale bars: 10 μm; (C,D) Higher magnification images of inner retina stained with Gallyas silver showing neurofibrillary tangle (NFT)-like structures in ganglion cell layer (GCL). (E) Immuofluorescence staining of AT100 mAb against phospho-tau (Thr212, Ser214) showing punctate aggregates and intracellular inclusions in INL. Images and data of panels (A,B) are adapted from Schön et al. (2012). Images and data of panels c-d are reproduced from Koronyo et al. (2017) with permission of ASCI via Copyright Clearance Center. Hyperphosphorylation of tau has been shown to drive the formation of fibrillar tau inclusions and neurofibrillary tangles, leading to disruptions in axonal transport as well as metabolic and oxidative stress, and is closely associated with neuronal death (Iqbal et al., 2009). Although several histological staining approaches have been utilized to confirm the presence of fibrillar inclusions of pTau in human AD retinas, thus far many have been unsuccessful (Schön et al., 2012; den Haan et al., 2018). To date, only one study using Gallyas silver staining detected NFT-like structures in postmortem retinas of definitive AD patients (Figures 4C,D; Koronyo et al., 2017). As mentioned above, there is an apparent gap in results obtained from different groups, possibly driven by the lack of standardized experimental procedures. For instance, the same antibodies against pTau reported to produce negative results by one group (Schön et al., 2012) detected pTau staining patterns similar to AT8-immunoreactivity in a later study (den Haan et al., 2018). Still, by utilizing AT100 antibody, two independent groups detected similar patterns of pTau in postmortem retinas from AD patients (Figure 4E; den Haan et al., 2018; Grimaldi et al., 2019). Future investigations would therefore be necessary to confirm the presence or absence of disease-associated tau conformers in the retinas of AD patients.\nMoreover, it is still unclear whether abnormal hyperphosphorylation of tau and/or formation of intracellular tangles have similar detrimental consequences in the retinas of patients as those observed in the brain. Analyses of retinal changes in AD transgenic mice support this putative association and will be discussed in the following sections. According to data from clinical studies and meta-analyses, levels of total tau and pTau in the CSF remain among the most reliable and sensitive biomarkers for both AD diagnosis and longitudinal monitoring of disease progression (Ibach et al., 2006; Welge et al., 2009; AlzBiomarker Database, 2018). Several lines of evidence indicate that CSF tau levels are significantly increased in AD patients (AlzBiomarker Database, 2018). Intriguingly, CSF total tau and pTau-181 concentrations were shown to correlate with retinal changes measured by fluorescent lifetime ophthalmoscopy, a technique suggested to detect the metabolic alterations of tissue represented by fluorescence decay of endogenous fluorophores (Jentsch et al., 2015). Nevertheless, the co-localization of pTau (den Haan et al., 2018; Grimaldi et al., 2019) and sites of neuronal loss in the retina (Koronyo et al., 2017; Asanad et al., 2019b; Grimaldi et al., 2019) are indicative of similar physiological vulnerabilities to pTau accumulation in both the retina and brain.\nRetinal disorders such as glaucoma and age-related macular degeneration (AMD) share a number of common features with AD retinal pathology including progressive deposition of protein aggregates, reactive gliosis and pro-inflammatory responses, metabolic dysfunction, oxidative stress, and retinal atrophy (Quigley, 1999; Naskar et al., 2002; Gupta et al., 2006; Guo et al., 2007; Tezel, 2011). In 2008, examination of retinal tauopathy in surgically removed tissue from human glaucoma cases revealed intense localization of AT8-positive pTau in horizontal cells residing in the OPL (Ibach et al., 2006; Gupta et al., 2008). It is hypothesized that the lateral arrangement of horizontal cell processes may predispose them to retinal stretch injury caused by glaucoma-related elevated intraocular pressure (IOP). Although no association was found between high IOP and dementia (Cesareo et al., 2015), it remains to be seen whether similar changes occur due to AD-associated ocular abnormalities. However, increased retinal pTau accumulation and atrophy following injury or due to other neurodegenerative disorders reveal the vulnerability of this neural tissue compartment to structural, functional, and neuropathological abnormalities (Green et al., 2010; Leger et al., 2011; Kim et al., 2017; Satue et al., 2017; Behbehani et al., 2018; Kim et al., 2019).\nAging remains the principal risk factor in AD and is tightly associated with several visual impairments. To date, only two studies have investigated the relationship between aging and total tau expression in the human retina. An early semi-quantitative analysis found no difference between tau immunoreactivity in post-mortem retinas from young and old healthy subjects, although age ranges were not clearly outlined (Loffler et al., 1995). Another study, examining retinas from enucleated eyes of patients with prior history of ocular disorders, reported a positive correlation between aging and total tau levels in RGCs in a subset of patients, while unable to find evidence of pTau (Leger et al., 2011). Such reports further showcase the disparity in these findings and reiterate the need for replication of these studies. Notably, the effects of aging on the abnormal accumulation of pTau in retinas of healthy individuals and/or patients also remains unexplored.\nAs it relates to tau imaging in the retina, there are currently no live imaging tools to specifically detect tau aggregates in the human retina. Preliminary results from a study that utilized spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescein (FAF) to visualize pathological tau aggregates in a cohort of PET-confirmed Alzheimer’s patients (Kayabasi, 2018) hints at the possibility of noninvasive live imaging and monitoring of neuropathological changes in the retina of MCI and AD patients; however, the specificity of the signal was not clear.\nOverall, it is apparent that investigations of retinal Aβ pathology and its relationship with cerebral amyloid plaque burden in AD patients are mounting. However, our understanding of retinal pTau accumulation and associations with brain NFT severity is much more limited. To date, only a few groups have successfully detected tau hyperphosphorylation in post-mortem human retinas from AD patients, and only one study has shown an association between retinal pTau and cerebral amyloid load in a small number of AD patients. Therefore, there is an urgent need for systematic and quantitative analyses of retinal pTau in larger cohorts as well as assessment of both the spatiotemporal and pathomechanistic properties of AD-related tau species in the retina and their relationship with brain disease and cognition."}