Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles.
Elevated levels of p25 and constitutive activation of CDK5 have been observed in AD brains. This has led to the hypothesis that increased p25 levels could promote neurofibrillary tangles (NFT) through CDK5-mediated hyperphosphorylation of tau, the principal component of NFTs. We examined p25 immunoreactivity in brains from sporadic and familial AD cases, as well as other neurologic diseases that exhibit NFT, such as Down's syndrome (DS), Pick's disease (Pick), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD). Neither the p25 immunoreactivity nor the p25/p35 ratio was elevated in the AD brains or in the other tauopathies (n = 34) compared with controls (n = 11). Although Abeta peptides have been suggested to activate calpain-mediated cleavage of p35 to p25 in cultured neurons, p25 levels in brains of TgCRND8 mice, which express high levels of brain Abeta peptides, were similar to those of non-Tg littermates. Our data suggest that high Abeta levels in brain do not activate p35 proteolysis, and p25 is unlikely to be a causative agent for NFT formation in AD or other tauopathies.
Tandon
Anurag
A
Departments of Medicine, University of Toronto, Toronto, Ontario, Canada. a.tandon@utoronto.ca
Yu
Haung
H
Wang
Linda
L
Rogaeva
Ekaterina
E
Sato
Christine
C
Chishti
M Azhar
MA
Kawarai
Toshitaka
T
Hasegawa
Hiroshi
H
Chen
Fusheng
F
Davies
Peter
P
Fraser
Paul E
PE
Westaway
David
D
St George-Hyslop
Peter H
PH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000096:biosynthesis*; D019636:Neurodegenerative Diseases / Q000201:enzymology*; D016874:Neurofibrillary Tangles
D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases