Abstract
When subjected to stress, terminally differentiated neurons are susceptible to reactivate the cell cycle and become hyperploid. This process is well documented in Alzheimer’s disease (AD), where it may participate in the etiology of the disease. However, despite its potential importance, the effects of neuronal hyperploidy (NH) on brain function and its relationship with AD remains obscure. An important step forward in our understanding of the pathological effect of NH has been the development of transgenic mice with neuronal expression of oncogenes as model systems of AD. The analysis of these mice has demonstrated that forced cell cycle reentry in neurons results in most hallmarks of AD, including neurofibrillary tangles, Aβ peptide deposits, gliosis, cognitive loss, and neuronal death. Nevertheless, in contrast to the pathological situation, where a relatively small proportion of neurons become hyperploid, neuronal cell cycle reentry in these mice is generalized. We have recently developed an in vitro system in which cell cycle is induced in a reduced proportion of differentiated neurons, mimicking the in vivo situation. This manipulation reveals that NH correlates with synaptic dysfunction and morphological changes in the affected neurons, and that membrane depolarization facilitates the survival of hyperploid neurons. This suggests that the integration of synaptically silent, hyperploid neurons in electrically active neural networks allows their survival while perturbing the normal functioning of the network itself, a hypothesis that we have tested in silico. In this perspective, we will discuss on these aspects trying to convince the reader that NH represents a relevant process in AD.
Highlights
As the nervous system ages, it undergoes functional alterations that diminish its performance and, as these changes increase, brain homeostasis becomes compromised resulting in neurodegenerative conditions including Alzheimer’s disease (AD)
We demonstrated that neuronal hyperploidization correlates with synaptic dysfunction (Barrio-Alonso et al, 2018), a known alteration occurring at early stages of AD (Scheff et al, 2006), and that membrane depolarization with high K+ facilitates the survival of hyperploid neurons without reversing synaptic dysfunction in these cells (Barrio-Alonso et al, 2018)
Since no significant differences were observed between cell somas of neurons lipofected with LacZ or K1 (Figure 1B), we concluded that the effect of T large antigen (TAg) on cell soma size is specific on its capacity to induce cell cycle reentry/hyperploidy (Barrio-Alonso et al, 2018)
Summary
As the nervous system ages, it undergoes functional alterations that diminish its performance and, as these changes increase, brain homeostasis becomes compromised resulting in neurodegenerative conditions including Alzheimer’s disease (AD). A plethora of neuroanatomical and functional alterations in the nervous system accompanying the process of aging and leading to AD-associated neurodegeneration has so far been described. Among these changes, DNA level variation and aneuploidy (Cuccaro et al, 2017; Shepherd et al, 2018) as well as cell cycle reentry in neurons. NH results in full DNA duplication (i.e., neuronal tetraploidy) This latter condition affects around 2– 3% of neurons in AD (Mosch et al, 2007; López-Sánchez et al, 2017), a proportion that increases to around 8% when specific neuronal subtypes are evaluated (López-Sánchez et al, 2017). Since the fate of hyperploid neurons is delayed cell death (Yang et al, 2001; Arendt et al, 2010) these numbers likely underestimate the actual proportion of AD-affected neurons undergoing NH
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