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

• Published in: Neurobiology of disease Vol. 215; p. 107057
• Main Authors: Santiago, Jessica, Pocevičiūtė, Dovilė, Vogel, Jacob, Brinkmalm, Gunnar, Wennström, Malin
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15.10.2025; Elsevier
• Subjects: Alzheimer's disease; Mass spectrometry; P-tau; Retina; Tau; DDA; PHFs; RD3; RT; RD4; IPL; TAR; DTT; IgG; Retina; Tau; mRNA; TFA; NBB; Aβ; LC-MS/MS; CA1; P-tau; m/z; T231; UHPLC; Alzheimer's disease; AGC; PBS; AD; S404; MS; PMD; HCD; DAPI; HT7; ACN; EDTA; 2N4R; PTMs; T181; NFTs; NC; DNA; LB; FA; MAPT; Mass spectrometry
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2025.107057

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. •Six phosphorylated tau sites were detected in human retina by mass spectrometry.·•Retinal p-tau S199/S202, T231, S396+T403/S404 were higher in cases with high Aβ load.•Retinal p-tau S396+T403/S404 showed associations with Aβ load and NFT Braak stage.•Correlation of retinal and brain p-tau of the same subjects linked retinal S396+T403/S404 to many hippocampal p-tau sites.