Cdk5 is a key factor in tau aggregation and tangle formation in vivo.
Tau aggregation is a common feature of neurodegenerative diseases such as Alzheimer's disease, and hyperphosphorylation of tau has been implicated as a fundamental pathogenic mechanism in this process. To examine the impact of cdk5 in tau aggregation and tangle formation, we crossed transgenic mice overexpressing the cdk5 activator p25, with transgenic mice overexpressing mutant (P301L) human tau. Tau was hyperphosphorylated at several sites in the double transgenics, and there was a highly significant accumulation of aggregated tau in brainstem and cortex. This was accompanied by increased numbers of silver-stained neurofibrillary tangles (NFTs). Insoluble tau was also associated with active GSK. Thus, cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. Kinase inhibitors may thus be beneficial therapeutically.
Noble
Wendy
W
Center for Dementia Research, Nathan S. Kline Institute, New York University, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Olm
Vicki
V
Takata
Kazuyuki
K
Casey
Evelyn
E
Mary
O
O
Meyerson
Jordana
J
Gaynor
Kate
K
LaFrancois
John
J
Wang
Lili
L
Kondo
Takayuki
T
Davies
Peter
P
Burns
Mark
M
Veeranna
Nixon
Ralph
R
Dickson
Dennis
D
Matsuoka
Yasuji
Y
Ahlijanian
Michael
M
Lau
Lit-Fui
LF
Duff
Karen
K
D000818:Animals; D001933:Brain Stem / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000201:enzymology*; D010766:Phosphorylation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3