Phospho-tau 217, phospho-tau 231 and phospho-tau 181 in cerebrospinal fluid and plasma are promising biomarkers for the diagnosis of Alzheimer's disease. All these p-tau proteins are detected in neurofibrillary tangles in brains obtained post-mortem from Alzheimer's disease patients. However, increases in p-tau levels in cerebrospinal fluid and plasma during the preclinical stage of Alzheimer's disease correlate with amyloid-β burden and precede neurofibrillary tangles in brains, suggesting that these p-tau proteins are indicative of amyloid-β-mediated brain pathology. In addition, phospho-tau 217 has greater sensitivity than phospho-tau 181, though it is unclear whether each of these p-tau variants contributes to the same or a different type of neuropathology prior to neurofibrillary tangle formation. In this study, we evaluated the intracerebral localization of p-tau in App knock-in mice with amyloid-β plaques without neurofibrillary tangle pathology (App^NLGF ), in App knock-in mice with increased amyloid-β levels without amyloid-β plaques (App^NL ) and in wild-type mice. Immunohistochemical analysis showed that phospho-tau 217 and phospho-tau 231 were detected only in App^NLGF mice as punctate structures around amyloid-β plaques, overlapping with the tau pathology marker, AT8 epitope phospho-tau 202/205/208. Moreover, phospho-tau 217 and phospho-tau 202/205/208 colocalized with the postsynaptic marker PSD95 and with a major tau kinase active, GSK3β. In contrast and similar to total tau, phospho-tau 181 signals were readily detectable as fibre structures in wild-type and App^NL mice and colocalized with an axonal marker neurofilament light chain. In App^NLGF mice, these phospho-tau 181-positive structures were disrupted around amyloid-β plaques and only partially overlapped with phospho-tau 217. These results indicate that phospho-tau 217, phospho-tau 231 and a part of phospho-tau 181 signals are markers of postsynaptic pathology around amyloid-β plaques, with phospho-tau 181 also being a marker of axonal abnormality caused by amyloid-β burden in brains.

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