This disease is a progressive insidious dementia that continues to severe debility and finally ends with death. It affects up to 16% of people over the age of 66 and nearly half of all individuals by the age of 86. There is selective loss of cortical neurons within the temporal, frontal lobes and hippocampus,. Depending upon the symptoms, onset and regional histopathology many variants of AD have been catalogued thus far. However, the resolution of early mechanisms will have to await a better understanding of the neuronal environment that allows for re-entry into the cell cycle.
The cell cycle hypothesis of AD proposes that the disease is caused by aberrant re-entry of different neuronal populations into the cell division cycle, following a 2-hit hypothesis. The cell cycle hypothesis of AD also attempts to explain for the characteristic senile plaques and the neurofibrillary tangles of AD pathology. The intracellular accumulation of highly phosphorylated tau is linked to the cell cycle and cell cycle dependent kinases. Other aberrations in cell cycle dynamics influence cell senescence, oxidative stress, and misregulated apoptosis. In particular, it is clear that oxidative stress is a pervasive feature in AD at all stages. Thus, the cell-cycle hypothesis of Alzheimer’s disease considers AD as a disease of deregulation of the cell cycle in neurons. The mechanisms of cell cycle activation probably do differ at many levels between the above three, but in AD this reentry is incomplete and results in stasis, dysfunction and death, a process that they term abortosis. However, there is evidence to suggest that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear at the very early stages of the disease, prior to the formation of plaques, and are characterized by aberrant expression of many cell cycle‐related proteins and inappropriate cell cycle control in specific vulnerable neuronal populations. Terminally differentiated neurons may re‐enter the cell cycle, which is regulated by the cellular redox state. The exact role of cell cycle re‐entry is unclear; however, data from several studies using cell culture and animal models support the notion that dysregulation of the cell cycle in neurons leads to the development of AD‐related pathology, such as hyperphosphorylation of tau and Aβ deposition, ultimately causing neuronal death. Indeed, once in the cycle, the cells die via apoptosis as they are unable to enter and complete M‐phase. Cell cycle re‐entry is also seen in mutant APP and, as in the human disease, occurs prior to the appearance of the histopathological hallmarks. Development of inhibitors of cell cycle re‐entry in neurons may therefore represent a novel approach to the treatment of AD. Neurons typically remain in G0, a nondividing, nonreplicating phase of the cell cycle. Neurons subject to loss of synaptic connections, chronic exposure to oxidative stress or stress hormones likeglucocorticoids will exit G0 and reenter into a cell cycle that is abortive and leads to cell death through apoptosis. The G0 to G1 transition in neurons is normally only observed for stressed neurons about to undergo apoptosis. Upon entering G1, these stressed neurons will be arrested at the G1 checkpoint by the absence of cyclin. In the past decade, research has shown that neuronal cell cycle reentry plays a fundamental role in the pathogenesis of AD.
The state of the cell cycle in any given environment has unique spatial and temporal control mechanisms. This is very important when cells are terminally differentiated. This reactivation of the cell cycle does not progress to completion but leads to stasis, dysfunction and cell loss. With markers from various phases of the cell cycle present in these vulnerable neurons, it is their belief that the synchronous nature of the cell cycle must be undermined in AD. That is the onset of the subsequent phase only after the completion of the prior phase of the cycle has been lost in AD. It is interesting that successful dysregulation of the cell division cycle along with an overriding of apoptosis is also seen as the main feature of oncogenic transformation and both features are seen also in AD. Modulation of one or multiple targets aimed at restoring the previous state of differentiation may in fact alter the natural course of this disease.
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