Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimer's disease-like tauopathy in female rats.
Aberrant mitosis occurs in many tauopathy-related neurodegenerative diseases and is believed to precede the formation of neurofibrillary tangles. In this study, we report for the first time that transient cerebral ischemia induces aberrant mitotic proteins and hyperphosphorylation of tau protein with neurofibrillary tangle-like conformational epitopes in adult female rat cortex. Following transient cerebral ischemia in rats, initiation of apoptosis precedes and is potentially integrated with subsequent aberrant mitosis and tau hyperphosphorylation. Furthermore, inhibition of mitosis-related cyclin-dependent kinases (Cdks) by roscovitine significantly reduced the hyperphosphorylation of tau. Administration of the female sex steroid and potent neuroprotective agent, 17beta-estradiol, reduced ischemia-reperfusion-induced cerebral damage and the subsequent aberrant mitosis and tauopathies. These results provide a neuropathological basis for the higher prevalence of dementia in stroke patients and support the hypothesis that apoptosis and aberrant mitosis are integrated pathological events in neurons that may play a critical role in the development of Alzheimer's disease and other tauopathy-related neuropathology.
Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Yi
Y
Wen
Shaohua
S
Yang
Ran
R
Liu
Anne Marie
AM
Brun-Zinkernagel
Peter
P
Koulen
James W
JW
Simpkins
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000737:chemistry; D017209:Apoptosis; D002545:Brain Ischemia / Q000378:metabolism*; D002453:Cell Cycle; D016923:Cell Death; D002540:Cerebral Cortex / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000939:Epitopes; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007511:Ischemia; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015427:Reperfusion Injury; D000077546:Roscovitine; D024801:Tauopathies / Q000378:metabolism*; D013997:Time Factors
D000941:Antigens; D004791:Enzyme Inhibitors; D000939:Epitopes; D011687:Purines; D000077546:Roscovitine; D004958:Estradiol; D011494:Protein Kinases