Biomarkers.

Background: Phosphorylated tau proteins accumulate in pathological aggregates which define neurodegenerative tauopathies, including Alzheimer's disease (AD). Insight into the early stages of tau polymerization/aggregation, including early hyperphosphorylation events, is critical for identification of biomarkers of incipient disease as well as novel therapy targets.

Method: We analyzed postmortem tissue sections of hippocampus from AD cases and middle frontal gyrus from non-AD cases with mainly 4R tau isoforms (progressive supranuclear palsy, PSP; corticobasal degeneration, CBD; aging related tau astrogliopathy, ARTAG) or 3R tau (Pick's disease, PiD). Immunohistochemical and multiple fluorescence methods were used to assess the labeling patterns of antibodies directed to phospo-epitopes within soluble non-fibrillar tau core (pSer262), both soluble and fibril core (pSer356), or outside of either core region (pSer202/pThr205, pThr231).

Result: In sections of hippocampus from AD cases, pSer262 and pSer356 stained punctate/granular tau aggregates in pretangles while pSer202/pThr205 and pThr231 antibodies stained tau in pretangles as well as classic NFT, neuritic component of plaques, and neuropil threads. Both pSer262 and pSer356 signals co-distributed with pSer202/pThr205 signal in pretangles but were rarely detected in pSer202/pThr205 immunoreactive classic NFT. In sections of middle frontal gyrus from PSP and CBD cases, tufted astrocytes and astrocytic plaques, respectively, were robustly labeled with the pSer202/pThr205 antibody but lacked significant immunoreactivity to pSer262 and pSer356 antibodies. Similarly, thorn shaped astrocytes in ARTAG cases were robustly labeled with the pSer202/pThr205 antibody but were weakly labeled with the pSer262 and pSer356 antibodies. Pick bodies were labeled robustly with the pSer202/pThr205 antibody, moderately with the pSer356 antibody, and weak and sparsely with the pSer262 antibody.

Conclusion: Antibodies directed against phosphorylated epitopes within core region of soluble and fibrillar tau distinguish hippocampal pretangles in AD and appear to have less affinity for tau pathology forms in non-AD tauopathies. Thus, they may be novel biomarkers for detecting early stages of neurofibrillary pathology development in AD.