Role of protein kinase B in Alzheimer's neurofibrillary pathology.
Protein kinase B (PKB) is an important intermediate in the phosphatidylinositol-3 kinase signaling cascade that acts to phosphorylate glycogen synthase kinase-3 (GSK-3) at its serine 9 residue, thereby inactivating it. Activated GSK-3 has been previously shown to be preferentially associated with neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. In the present study, we performed immunohistochemistry with an antibody to the active form of PKB in brains with different stages of neurofibrillary degeneration. We found that the amount of activated PKB (p-Thr308) increased in correlation to the progressive sequence of AT8 immunoreactivity and neurofibrillary changes assessed according to Braak's criteria. By confocal microscopy, activated PKB (p-Thr308) was found to appear in particular in neurons that are known to later develop NFTs in AD. Western blotting showed that activated PKB was increased by more than 50% in the 16,000- g supernatants of AD brains as compared with normal aged and Huntington's disease controls. This increase in PKB levels corresponded with a several-fold increase in the levels of total tau and abnormally hyperphosphorylated tau at the Tau-1 site. These studies suggest the involvement of PKB/GSK-3 signaling in Alzheimer neurofibrillary degeneration.
Pei
Jin-Jing
JJ
Neurotec, Section for Experimental Geriatrics, Novum, Karolinska Institutet, KFC Plan 4, 141 86 Huddinge, Sweden. Jin-Jing.Pei@neurotec.ki.se
Khatoon
Sabiha
S
An
Wen-Lin
WL
Nordlinder
Maria
M
Tanaka
Toshihisa
T
Braak
Heiko
H
Tsujio
Ichiro
I
Takeda
Masatoshi
M
Alafuzoff
Irina
I
Winblad
Bengt
B
Cowburn
Richard F
RF
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D016875:tau Proteins / Q000378:metabolism
D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D016875:tau Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3