Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Ophthalmology
• Pathology

Background:

• Phosphorylated tau (p-τ) protein accumulation is a hallmark of Alzheimer's disease (AD) and tauopathies.
• Retinal neurons can accumulate p-τ, contributing to visual disturbances.
• Primary retinal tauopathy (PReT) is characterized by distinct stages of p-τ aggregation in the human retina.

Purpose of the Study:

• To investigate the role of p-τ pathology in visual performance.
• To explore the relationship between retinal and cerebral p-τ pathology.
• To differentiate human PReT from cerebral tauopathies like AD and primary age-related tauopathy (PART).

Main Methods:

• Analysis of p-τ phosphorylation sites and conformational epitopes in human retinal tauopathy.
• Western blot analysis to compare retinal and cerebral p-τ molecular patterns.
• Utilizing transgenic mouse models (TAU58) to study retinal tau pathology and propagation after AD brain lysate injection.

Main Results:

• Human retinal tauopathy shows distinct p-τ molecular patterns and lacks fibrillar lesions, differentiating it from AD.
• PReT stages correlate with visual performance decline and dementia symptoms.
• In mice, retinal tau pathology is linked to ganglion cell loss, and tau pathology can propagate from retina to brain.

Conclusions:

• Human PReT is a distinct entity from AD, particularly in younger individuals, characterized by non-fibrillar p-τ.
• Retinal tau pathology can propagate to the brain, suggesting a potential pathway for neurodegeneration.
• PReT's association with visual impairment and dementia warrants further investigation and may precede AD or other tauopathies.