Evidence for the progression through S-phase in the ectopic cell cycle re-entry of neurons in Alzheimer disease.
Aberrant neuronal re-entry into the cell cycle is emerging as a potential pathological mechanism in Alzheimer disease (AD). However, while cyclins, cyclin dependent kinases (CDKs), and other mitotic factors are ectopically expressed in neurons, many of these proteins are also involved in other pathological and physiological processes, generating continued debate on whether such markers are truly indicative of a bona fide cell cycle process. To address this issue, here we analyzed one of the minichromosome maintenance (Mcm) proteins that plays a role in DNA replication and becomes phosphorylated by the S-phase promoting CDKs and Cdc7 during DNA synthesis. We found phosphorylated Mcm2 (pMcm2) markedly associated with neurofibrillary tangles, neuropil threads, and dystrophic neurites in AD but not in aged-matched controls. These data not only provide further evidence for cell cycle aberrations in AD, but the cytoplasmic, rather than nuclear, localization of pMcm2 suggests an abnormal cellular distribution of this important replication factor in AD that may explain resultant cell cycle stasis and consequent neuronal degeneration.
Bonda
David J
DJ
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Evans
Teresa A
TA
Santocanale
Corrado
C
Llosá
Jesús Catalá
JC
Viña
Jose
J
Bajic
Vladan  P
V
Castellani
Rudy J
RJ
Siedlak
Sandra L
SL
Perry
George
G
Smith
Mark A
MA
Lee
Hyoung-gon
HG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D009474:Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid; D021381:Protein Transport; D016196:S Phase / Q000502:physiology*
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2