Long-Term In Vivo Imaging of Fibrillar Tau in the Retina of P301S Transgenic Mice

Abstract

Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer's disease, pathological alterations in the retina are discussed as potential biomarkers to improve early diagnosis of the disease. Using mice expressing human mutant P301S tau, we demonstrate for the first time a straightforward optical approach for the in vivo detection of fibrillar tau in the retina. Longitudinal examinations of individual animals revealed the fate of single cells containing fibrillar tau and the progression of tau pathology over several months. This technique is most suitable to monitor therapeutic interventions aimed at reducing the accumulation of fibrillar tau. In order to evaluate if this approach can be translated to human diagnosis, we tried to detect fibrillar protein aggregates in the post-mortem retinas of patients that had suffered from Alzheimer's disease or Progressive Supranuclear Palsy. Even though we could detect hyperphosphorylated tau, we did not observe any fibrillar tau or Aß aggregates. In contradiction to previous studies, our observations do not support the notion that Aβ or tau in the retina are of diagnostic value in Alzheimer's disease.

Melanopsin retinal ganglion cell loss in Alzheimer disease

“…Interestingly, a more recent study also documented phosphorylated‐tau deposition in AD human retinas 71. Importantly, Aβ deposits were frequently found inside and around mRGCs.…”

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

“…A couple of studies that were unable to detect Aβ in the human AD retina analyzed horizontal cross sections spanning a narrow strip from the nasal to temporal quadrants (41,43), rather than screening large regions in flat mounts, thus limiting their analysis to regions that are largely spared of amyloid pathology in AD patients. Therefore, while Ho and colleagues (43) were unable to detect Aβ, p-tau, or α-synuclein in any ocular tissue of AD or Parkinson's disease (PD) patients, considerably more independent studies in fact reported the presence of Aβ deposits in the retina and lenses (11,39,40,42,51,83) as well as identified p-tau (41) and α-synuclein (84) in the retinas of AD and PD patients, respectively.…”

“…Subsequent studies have corroborated these findings by demonstrating the existence of retinal Aβ deposits, identifying increased Aβ peptides in the human retina by biochemical analysis (albeit to a lower extent than those seen in neocortical tissues), and, moreover, showing the presence of pTau in retinal tissues of AD patients (39,41,42). Although a few studies were unable to detect Aβ (41,43) or pTau (43) in the human AD retina, several independent groups confirmed their existence by applying specific tissue processing and immunostaining protocols and screening large retinal regions that had previously been overlooked (11,26,(39)(40)(41)(42). In a recent study, notable Aβ accumulation inside and around degenerating melanopsin-containing RGCs (mRGCs), photoreceptors known to drive circadian photoentrainment, was found in AD patients (26).…”

“…While the hallmark pathologies of AD have long been established in the brain, their manifestation in the human retina is a recent finding (11,26,(39)(40)(41)(42). We previously identified Aβ plaque pathology in postmortem retinas of definite AD patients as well as in early-stage cases (40).…”

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

“…In a subset of animals, we also labeled NFTs in vivo using i.v. injections of the Congo red derivate methoxy-X04 in anesthetized animals (22,23) (Fig. S5).…”