Cell cycle re-entry mediated neurodegeneration and its treatment role in the pathogenesis of Alzheimer's disease

Abstract

As one of the earliest pathologic changes, the aberrant re-expression of many cell cycle -related proteins and inappropriate cell cycle control in specific vulnerable neuronal populations in Alzheimer's disease (AD) is emerging as an important component in the pathogenesis leading to AD and other neurodegenerative diseases. These events are clearly representative of a true cell cycle, rather than epiphenomena of other processes since, in AD and other neurodegenerative diseases, there is a true mitotic alteration that leads to DNA replication. While the exact role of cell cycle reentry is unclear, recent studies using cell culture and animal models strongly support the notion that the dysregulation of cell cycle in neurons leads to the development of AD-related pathology such as hyperphosphorylation of tau and amyloid-β deposition and ultimately causes neuronal cell death. Importantly, cell cycle re-entry is also evident in mutant amyloid-β protein precursor and tau transgenic mice and, as in human disease, occurs prior to the development of the pathological hallmarks, neurofibrillary tangles and amyloid-β plaques. Therefore, the study of aberrant cell cycle regulation in model cellular and animal systems may provide extremely important insights into the pathogenesis of AD while serving as a means to test novel therapeutic approaches. KeywordsAlzheimer's disease; amyloid-β; cell cycle; neurodegeneration; tau phosphorylation CELL CYCLE ALTERATIONS IN ALZHEIMER'S DISEASE AND OTHER NEURODEGENERATIVE DISEASESPrimary neurons in the normal brain are viewed as being quiescent and in G 0 (Obrenovich et al., 2005). However, in Alzheimer's disease (AD), multiple lines of evidence suggest that neurons vulnerable to degeneration emerge from this postmitotic state -phenotypically suggestive of cells that are cycling, rather than the normal terminally differentiated nondividing state (Arendt et al

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

“…It is well known that retinoblastoma protein phosphorylation constitutes a restrictive point in the process of cell-cycle re-entry. This process is mediated by cyclins, specifically cyclin D, and can be phosphorylated by E, favoring the release of E2F-1 and cell-cycle progression or apoptosis [59][60][61][62][63]. However, recent studies have reported that Rb may also be phosphorylated by other enzymes such as CDK5, GSK3b, and p38 [34,42,56,63].…”

Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease

“…Ironically, instead of dividing, these neurons apparently die up to a year after exiting G0 of the cell cycle (Greene et al, 2007;Herrup et al, 2004;Lee et al, 2009;Vincent et al, 1996). This ectopic cell cycle re-entry (CCR) evidently accounts for a significant fraction of the cortical neurons that are lost in AD (Arendt et al, 2010) and has also been observed in numerous mouse models of the disease (Li et al, 2011).…”

Altered Calmodulin Degradation and Signaling in Non-Neuronal Cells from Alzheimer’s Disease Patients

“…Interestingly, the distinct Ca 2+ response of AD was associated with enhanced cell proliferation compared to control lymphoblasts from age-matched individuals [16,17]. These features were considered as peripheral signs of the disease, as current evidence relates the process of neuronal apoptosis occurring in AD to the aberrant reentry of differentiated neurons into the cell cycle [18][19][20].…”