Basic Science and Pathogenesis

The accumulation of abnormal phosphorylated tau (p-τ) protein in neurons is a hallmark of Alzheimer's disease (AD) and primary tauopathies. Both conditions involve p-τ accumulation in retinal neurons. Here, we explore the role of p-τ pathology in visual performance and the interplay between retinal and cerebral p-τ pathology. In the human retina, p-τ is frequently found. This retinal tauopathy evolves in three stages: stage 1 involves p-τ aggregates in the outer plexiform layer, stage 2 affects neurons in the inner nuclear layer, and stage 3 involves the inner plexiform layer. Various phosphorylation sites (S202/T205, T231, S396/404) and conformational τ epitopes are present in human retinal tauopathy, but no argyrophilic fibrils are seen. Western blot analysis shows a distinct molecular pattern of p-τ species in the retina compared to cerebral tauopathies like AD and primary age-related tauopathy (PART). The stages of this primary retinal tauopathy (PReT) correlate with altered visual performance and dementia symptoms. In transgenic mouse models, p-τ is prominent in retinal ganglion cells, which can develop fibrillar aggregates, unlike in human retinal tauopathy. In the TAU58 mouse model, tauopathic changes in the retina are associated with ganglion cell loss. TAU58 mice show enhanced tau pathology in the retina after AD brain lysate injection, with increased tau changes in the contralateral superior colliculus, suggesting propagation from retina to brain. Lysates from a Braak stage I PART case did not induce propagation but accelerated seeding in the retina. These findings suggest that human PReT, with its low levels of p-τ and lack of fibrillar p-τ lesions, is a separate entity from AD, especially in young individuals. However, propagation of p-τ pathology from retina to brain is possible. PReT's association with visual worsening in humans and reduced retinal ganglion cells in mice needs further exploration. PReT may also be a prerequisite for retinal involvement in AD and primary tauopathies, as indicated by its association with dementia symptoms. Funding: SAO/FRA 2020/017.