Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain
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RESEARCH
Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain Kanta Horie1, Nicolas R. Barthélemy1*, Nipun Mallipeddi1, Yan Li2, Erin E. Franklin3,5, Richard J. Perrin1,3,4,5, Randall J. Bateman1,4,5 and Chihiro Sato1*
Abstract Alzheimer’s disease (AD) neuropathologic change is characterized by amyloid plaques and neurofibrillary tangles (NFTs) that consist of aggregated amyloid beta (Abeta) and hyperphosphorylated tau proteins (p-tau), respectively. Although the global relationship between Abeta and p-tau has been studied for decades, it is still unclear whether a regional correlation exists between Abeta and p-tau in the human brain. Recent studies in cerebrospinal fluid (CSF) have suggested that tau phosphorylation at specific sites such as T217 is modified at an early stage of AD when amyloid plaques become detectable. We applied biochemical and mass spectrometry methods in human brain samples with and without Abeta plaque pathology to measure site-specific phosphorylation occupancies in soluble and insoluble tau. Our quantitative results identified multiple residues specifically hyper-phosphorylated in AD, including at sites T111, T153, S184 (or S185), T205, S208, T217, S262, and S285 in brain soluble tau. In contrast, the most enriched phosphorylated residues in brain insoluble tau were T111, S113, T153, T181, S199, S202, T205, T217, T231, S262, and S396. Tau phosphorylation occupancies in the insoluble fraction were relatively constant across brain regions, suggesting that tau has a consistent phosphorylation pattern once it has aggregated into NFTs. We did not find regional association between Abeta42 and insoluble tau. However, the phosphorylation profile of soluble tau in AD brain was highly correlated to that in AD CSF, which was analyzed in a previous study. We also found a higher regional association between total Abeta42 and soluble tau phosphorylation occupancy at residues T111, T153 and T217 in the brain. This study provides insights into regional interactions between amyloidosis and specific tau phosphorylated residues in the human brain and may explain the specific increases of tau species phosphorylation observed in AD CSF.
Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects stereotyped regions of the brain and, over many years, leads to synaptic impairment and neurological decline. The neuropathological hallmarks of AD are amyloid plaques that accumulate *Correspondence: [email protected]; [email protected] 1 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA Full list of author information is available at the end of the article
early in AD, and neurofibrillary tangles (NFTs) that accumulate later and correlate more closely with clinical impairment. Plaques and NFTs are composed of aggregated amyloid beta (Abeta) and hyperphosphorylated tau (p-tau), respectively. A potential link and causality between Abeta and p-tau has been studied over two
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