Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice.
Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles.
Bian
Feng
F
CNS Pharmacology, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. feng.bian@pfizer.com
Nath
Rathna
R
Sobocinski
Gregg
G
Booher
Robert N
RN
Lipinski
William J
WJ
Callahan
Michael J
MJ
Pack
Amy
A
Wang
Kevin K-W
KK
Walker
Lary C
LC
D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology*; D015153:Blotting, Western; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D020820:Dyskinesias / Q000235:genetics* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology; D010525:Peripheral Nerves / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012584:Sciatic Nerve / Q000473:pathology; D019076:Transgenes / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
D009419:Nerve Tissue Proteins; D010982:Platelet-Derived Growth Factor; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases