Tau in Alzheimer's disease and Down's syndrome is insoluble and abnormally phosphorylated.
Some investigators have described the presence in Alzheimer's disease brain extracts of several abnormal forms of the microtubule-associated protein tau, based on their unusual mobility in SDS/PAGE. It has been proposed that these abnormal forms of tau may be the result of aberrant tau phosphorylation. In this study we show that tau in extracts of Alzheimer's disease brain can be separated into two fractions based upon its solubility (100,000 g x 1 h supernatant) in non-denaturing conditions (100 mM-Mes, pH 6.5, 0.5 mM-MgCl2, 1 mM-EGTA and 1 M-NaCl). The tau isoforms with decreased mobility in SDS/PAGE are predominantly in an insoluble fraction, whereas the soluble tau is indistinguishable by its mobility in SDS/PAGE from tau in soluble extracts of control brain. Insoluble tau displaying abnormal mobility on SDS/PAGE was only found in Alzheimer and adult Down's syndrome brains and was absent from the brains of age-matched controls and from foetal and infant Down's syndrome brains. There was a good correlation between the presence of insoluble tau in brain extracts and the abundance of neurofibrillary tangles and senile neuritic plaques. The monoclonal antibody Tau. 1 stained insoluble tau on Western blots only after treatment of the nitrocellulose transfers with alkaline phosphatase, implying that this insoluble tau is in a particular state of phosphorylation. We conclude that, in Alzheimer's disease, a fraction of tau has a modified phosphorylation state and a decreased solubility; these modifications may precede formation of the neurofibrillary tangles characteristic of Alzheimer's disease and Down's syndrome in adults.
Hanger
D P
DP
Department of Neuroscience, Institute of Psychiatry, Denmark Hill, London, U.K.
Brion
J P
JP
Gallo
J M
JM
Cairns
N J
NJ
Luthert
P J
PJ
Anderton
B H
BH
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D004314:Down Syndrome / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D008875:Middle Aged; D009454:Neurofibrils / Q000473:pathology; D010766:Phosphorylation; D012995:Solubility; D016875:tau Proteins
D000911:Antibodies, Monoclonal; D008869:Microtubule-Associated Proteins; D016875:tau Proteins