Retinal tau phosphorylation in Alzheimer's disease: A mass spectrometry study

Most neurodegenerative diseases, including Alzheimer's disease (AD) and multiple sclerosis (MS), feature abnormal tau phosphorylation (p-tau) in the brain. Prior immunostaining studies have shown p-tau accumulation in the AD retina, suggesting it may mirror brain tau pathology.

We used mass spectrometry to quantify p-tau peptides in matched retinal and hippocampal samples from non-demented controls (NC, n = 8), AD (n = 12), and MS (n = 4). We compared p-tau levels across diagnoses and analysed correlations between retinal p-tau variants, hippocampal p-tau, and neuropathological changes.

Tau peptides phosphorylated at T181, S199/S202, T231, T231 + T235, S396 + T403/S404, and T403/S404 were detected in retinas. Total tau phosphorylation and phosphorylation at S199/S202 and T231 were significantly higher in AD cases compared to NC. These two, along with p-tau S396 + T403/S404, were also higher in cases with high amyloid-beta (Aβ) Braak stages compared to those with low Aβ Braak stages. Higher Aβ stages were also correlated with higher peak intensities of p-tau S199/S202 and S396 + T403/S404, and retinal p-tau S396 + T403/S404 and T403/S404 correlated with neurofibrillary tangle (NFT) Braak stages. Additionally, p-tau S396 + T403/S404 in the retina was associated with corresponding phosphorylation in the hippocampus.

Our findings reveal both overlapping and distinct p-tau patterns in retina and hippocampus, with a notable link for p-tau S396 + T403/S404. This enhances our understanding of tauopathies in both tissues and supports retinal tau as a promising biomarker for AD diagnosis and monitoring.