Elevation of pS262-Tau and Demethylated PP2A in Retina Occurs Earlier than in Hippocampus During Hyperhomocysteinemia.

Hyperhomocysteinemia is an independent risk factor of Alzheimer's disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage.