Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles.
Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are integral players in the proper development of the mammalian central nervous system. Proteolytic cleavage of p35 generates p25, leading to aberrant Cdk5 activation. The accumulation of p25 is implicated in several neurodegenerative diseases. In primary neurons, p25 causes apoptosis and tau hyperphosphorylation. Current mouse models expressing p25, however, fail to rigorously recapitulate these phenotypes in vivo. Here, we generated inducible transgenic mouse lines overexpressing p25 in the postnatal forebrain. Induction of p25 preferentially directed Cdk5 to pathological substrates. These animals exhibited neuronal loss in the cortex and hippocampus, accompanied by forebrain atrophy, astrogliosis, and caspase-3 activation. Endogenous tau was hyperphosphorylated at many epitopes, aggregated tau accumulated, and neurofibrillary pathology developed progressively in these animals. Our cumulative findings provide compelling evidence that in vivo deregulation of Cdk5 by p25 plays a causative role in neurodegeneration and the development of neurofibrillary pathology.
Cruz
Jonathan C
JC
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. jonathan_cruz@hms.harvard.edu
Tseng
Huang-Chun
HC
Goldman
Joseph A
JA
Shih
Heather
H
Tsai
Li-Huei
LH
D000818:Animals; D001921:Brain / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002458:Cell Fractionation / Q000379:methods; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D003902:Detergents / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D007930:Leucine / Q000235:genetics; D008164:Luminescent Proteins / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D008870:Microtubules / Q000378:metabolism; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000201:enzymology* / Q000209:etiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D011392:Proline / Q000235:genetics; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
D003902:Detergents; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D049452:Green Fluorescent Proteins; C025231:sarkosyl; D011392:Proline; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D007930:Leucine; D012521:Sarcosine