Retinal A~ and tau-pathology and its link to Alzheimer’s disease’ (SAO)

Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder leading to dementia. Amyloid β-protein (Aβ) and abnormal phosphorylated τ-protein (p-τ) are the pathological hallmark proteins. Recently, Aβ and p-τ aggregates were found in the retina of AD patients. It not yet clear when in the pathogenesis of AD retinal lesions occur or whether p-τ lesions can also be related to other degenerative diseases in the retina such as in the brain. Here, we hypothesize that there is a specific AD-related pattern of Aβ and p-τ pathology in the retina and that this pathology can start in non-demented individuals in preclinical AD. Accordingly, our 1st objective is to analyze age distribution and topographical patterns of retinal Aβ and p-τ pathology in elderly individuals and AD patients. This is important since imaging techniques focusing on the detection of retinal Aβ are tested as possible biomarkers for AD.
Recently, we have shown in amyloid precursor protein (APP)xτ-transgenic mice that Aβ accelerates p-τ pathology in the brain via a link of both proteins to prion protein (PrP). Similar interactions of Aβ and p-τ with PrP were seen in AD patients. Whether a similar link can also be observed in the retina is not clear. Based on our results in the brains of APPxτ transgenic mice we hypothesize that Aβ can accelerate retinal p-τ pathology via interactions with PrP. Thus, the 2nd objective is to determine cooperative effects between Aβ and p-τ in the retina, presumably indicative for an AD-related pathogenetic mechanism.
Spreading is currently considered as an important mechanism explaining the expansion of p-τ and Aβ pathology from one brain region into others. This leads to the hypothesis that p-τ and/or Aβ aggregates in the retina lead to a spreading of the respective protein aggregates into the brain. Accordingly, our 3rd objective is to test whether the retina is involved in AD-like spreading of Aβ and p-τ aggregates.
By addressing these objectives, we will be able to clarify whether there is a specific AD-related pattern of retinal Aβ and p-τ pathology, whether these pathologies start already in preclinical AD, and whether the presence of AD-related pathomechanisms (cooperation of Aβ and p-τ, spreading) in the retina confirms a possible involvement of the retina in AD.
To address objective 1 we want to determine the prevalence and topographical pattern of Aβ and p-τ pathology in the retina of 185 elderly individuals and 15 AD patients using immunohistochemistry.
Objective 2 will be addressed by analyzing the eyes of APP-, τ- and APPxτ-transgenic mice. Immunohistochemical and biochemical analysis will allow us to clarify whether APPxτ-transgenic mice will have more p-τ and /or Aβ pathology than the respective single transgenic mice.
Finally, objective 3 will be addressed by testing whether Aβ and p-τ seeds injected into the subretinal zone induce or accelerate Aβ or p-τ pathology in the brain regions to which the optic nerve projects.