Phosphorylation of different tau sites during progression of Alzheimer's disease.
Alzheimer's disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls. Allo- and isocortical brain regions were evaluated applying rater-independent automated quantification based on digital image analysis. We found that the level of ptau at several residues, like Ser199, Ser202/Thr205, and Ser422 was similar in healthy controls and Braak stages I to IV but was increased in Braak stage V/VI throughout the entire isocortex and transentorhinal cortex. Quantification of ThioS-stained plaques showed a similar pattern. Only tau phosphorylation at Tyr18 and Thr231 was already significantly increased in the transentorhinal region at Braak stage III/IV and hence showed a progressive increase with increasing Braak stages. Additionally, the increase in phosphorylation relative to controls was highest at Tyr18, Thr231 and Ser199. By contrast, Ser396 tau and Ser262 tau showed only a weak phosphorylation in all analyzed brain regions and only minor progression. Our results suggest that the ptau burden in the isocortex is comparable between all analyzed ptau sites when using a quantitative approach while levels of ptau at Tyr18 or Thr231 in the transentorhinal region are different between all Braak stages. Hence these sites could be crucial in the pathogenesis of AD already at early stages and therefore represent putative novel therapeutic targets.
['Neddens|Joerg|J|', 'Temmel|Magdalena|M|', 'Flunkert|Stefanie|S|', 'Kerschbaumer|Bianca|B|', 'Hoeller|Christina|C|', 'Loeffler|Tina|T|', 'Niederkofler|Vera|V|', 'Daum|Guenther|G|', 'Attems|Johannes|J|', 'Hutter-Paier|Birgit|B|0000-0003-3699-2227']
D000368:Aged D000369:Aged, 80 and over D000544:Alzheimer Disease D001921:Brain D018450:Disease Progression D005260:Female D006801:Humans D008297:Male D008875:Middle Aged D010766:Phosphorylation D011569:Psychiatric Status Rating Scales D012694:Serine D018709:Statistics, Nonparametric D013912:Threonine D014443:Tyrosine D016875:tau Proteins
Phosphorylation Transentorhinal region Cingulate Frontal Immunofluorescent labeling Microtubule-associated protein tau Occipital and temporal cortex