Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats.
Although neurofibrillary tangle (NFT) formation is a central event in both familial and sporadic Alzheimer's disease (AD), neither cellular origin nor functional consequence of the NFTs are fully understood. This largely is due to the lack of available in vivo models for neurofibrillary degeneration (NFD). NFTs have only been identified in transgenic mice, bearing a transgene for a rare hereditary neurodegenerative disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP17). Epidemiological evidence suggests a much higher occurrence of dementia in stroke patients. This may represent the underlying cause of the pathogenesis of sporadic AD, which accounts for the majority of AD cases. We examined pathological markers of AD in a rodent stroke model. Here we show that after transient cerebral ischemia, hyperphosphorylated tau accumulates in neurons of the cerebral cortex in the ischemic area, forms filaments similar to those present in human neurodegenerative tauopathies and colocalizes with markers of apoptosis. As a potential underlying mechanism, we were able to determine that transient ischemia induced tau hyperphosphorylation and NFT-like conformations are associated with aberrant activation of cyclin dependent kinase 5 (Cdk5) and can be rescued by delivery of a potent, but non-specific cyclin dependent kinase inhibitor, roscovitine to the brain. Our study further indicates that accumulation of p35 and its calpain-mediated cleavage product, p25 may account for the deregulation of Cdk5 induced by transient ischemia. We conclude that Cdk5 may be the principal protein kinase responsible for tau hyperphosphorylation and may be a hallmark of the tauopathies in this stroke model.
Wen
Yi
Y
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Yang
Shao-Hua
SH
Liu
Ran
R
Perez
Evelyn J
EJ
Brun-Zinkernagel
Anne Marie
AM
Koulen
Peter
P
Simpkins
James W
JW
D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D005260:Female; D007839:Functional Laterality; D002546:Ischemic Attack, Transient / Q000473:pathology*; D016874:Neurofibrillary Tangles / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D024801:Tauopathies / Q000473:pathology
D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases