Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration.

The American Journal of Pathology
David MuyllaertF Van Leuven

Abstract

The cyclin-dependent kinase cdk5 is atypically active in postmitotic neurons and enigmatic among the kinases proposed as molecular actors in neurodegeneration. We generated transgenic mice to express p25, the N-terminally truncated p35 activator of cdk5, in forebrain under tetracycline control (TET-off). Neuronal expression of p25 (p25(ON)) caused high mortality postnatally and early in life. Mortality was completely prevented by administration of doxycycline in the drinking water of pregnant dams and litters until P42, allowing us to study the action of p25 in adult mouse forebrain. Neuronal p25 triggered neurodegeneration and also microgliosis, rapidly and intensely in hippocampus and cortex. Progressive neurodegeneration was severe with marked neuron loss, causing brain atrophy (40% loss at age 5 months) with nearly complete elimination of the hippocampus. Neurodegeneration did not involve phosphorylation of protein tau or generation of amyloid peptide. Degenerating neurons did not stain for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling or activated caspase-3 but were marked by FluoroJadeB in early stages. Diseased neurons were always closely associated with activated microglia already very early in t...Continue Reading

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Citations

Oct 23, 2010·Molecular Psychiatry·K N ManolopoulosA Barthel
Apr 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Justin V LouisVeerle Janssens
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Dec 24, 2018·Human Molecular Genetics·Jana SchmidtThorsten Schmidt
Apr 20, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yong HeYafang Hu

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