Evidence for the progression through S-phase in the ectopic cell cycle re-entry of neurons in Alzheimer disease

Abstract

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.

A novel hypothesis for Alzheimer disease based on neuronal tetraploidy induced by p75NTR

“…25 Apart from the observation that G 2 /M-specific regulators are detected in AD, direct evidence for S-phase progression in AD-affected neurons has also been reported. 26,27 These observations are consistent with the presence of hyperphosphorylated Rb and E2F1 immunoreactivity in AD brain, associated with neurons surrounding Aβ-containing plaques but not in NFT containing neurons, 28 thus suggesting that E2F1 activation takes place prior to the presence of neuropathological signs in neurons. Nevertheless, in other cases hyperphosphorylated Rb has also been observed in neurons containing NFTs.…”

“…119,120 Besides being a source of superoxide anions 121 and pathogenic cytokines, 122 microglial cells can also express NGF/proNGF, [123][124][125][126] thus triggering NGF-dependent neurodegeneration. Microglial cells activated by inflammatory signals, including the Aβ fragment Aβ [25][26][27][28][29][30][31][32][33][34][35] , have been shown to express NGF, 127 and they induce cell cycle re-entry and cell death of cortical neurons in vitro. 128 regulating several cellular functions including cell survival, cell death and axonal outgrowth.…”

“…57 Indeed, the presence of double nucleated neurons, likely derived from nuclear division without cytokinesis, has been reported to occur in AD. 160 Interestingly, different polymorphisms of BDNF can confer risk of suffering AD, although their association with Interestingly, Aβ [25][26][27][28][29][30][31][32][33][34][35] can also induce NGF in astrocytes, which in turn triggers hyperphosphorylation of Tau in neurons, mediated by p75 NTR . 129 This suggests that general gliosis may participate in the progression of AD.…”

成熟神经元的细胞周期再活化与大脑可塑性、 神经元损伤和神经退行性疾病的关系

“…Further evidence supports that neurons in AD reenter the cell cycle and progress through the S phase activating a specific component of the DNA replication machinery (MCM2 protein), producing cell cycle stasis with the consequent expression of AD markers and the subsequent neuronal degeneration [71] . In AD, accumulating evidence indicates that although vulnerable neurons proceed as far as DNA replication and entry into the S phase can be demonstrated in dying neurons, progression through the M phase has never been reported.…”

FE65 regulates and interacts with the Bloom syndrome protein in dynamic nuclear spheres – potential relevance to Alzheimer's disease

“…Cell cycle re-entry in neurons occurs in AD (Herrup, 2012;Lopes et al, 2009b) and results in neuronal cell death (Folch et al, 2011). Cell cycle re-entry in AD is characterized by the association of MCM2 with neurofibrillary tangles (Bonda et al, 2009), kinase upregulation, cytoskeletal alterations (Lopes et al, 2009b) and re-expression of cell cycle related proteins like CDK11 (Bajić et al, 2011). The re-entry was also reported not to be induced by Ab or Tau pathology (Lopes et al, 2009a).…”