Pathological Aspects of Neuronal Hyperploidization in Alzheimer’s Disease Evidenced by Computer Simulation

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.

E2F4 as a single multifactorial target against Alzheimer’s disease

“…Of relevance is also the demonstration that NT is prevented by neuronal E2F4DN expression. Cell cycle reentry, together with neuroinflammation, has been proposed to be major drivers of AD ( 10 ), likely due to its capacity to induce NFTs, extracellular deposits of Aβ, gliosis, synaptic dysfunction and delayed neuronal cell death [reviewed by ( 12 )]. Furthermore, NT triggers synaptic dysfunction ( 83 ) and may affect neuronal structure and function ( 12 ).…”

“…Cell cycle reentry, together with neuroinflammation, has been proposed to be major drivers of AD ( 10 ), likely due to its capacity to induce NFTs, extracellular deposits of Aβ, gliosis, synaptic dysfunction and delayed neuronal cell death [reviewed by ( 12 )]. Furthermore, NT triggers synaptic dysfunction ( 83 ) and may affect neuronal structure and function ( 12 ). Our results are consistent with the observation that prevention of NT in the cerebral cortex of aged E2f1 -/- mice correlates with enhanced cognition ( 71 ).…”

“…These processes interact with each other resulting in synergistic effects. For instance, neuronal cell cycle re-entry can induce NFTs, extracellular deposits of Aβ, gliosis, synaptic dysfunction and delayed neuronal cell death, which all together lead to cognitive deficits [reviewed by ( 12 )]. Additionally, oxidative stress affects synaptic activity and triggers abnormal cellular metabolism that in turn could affect the production and accumulation of Aβ and hyperphosphorylated tau ( 8 ).…”

Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex

“…that immediately followed and were truncated by DOWN states. DOWN-state responses were aligned by the delta peak or the end of the DOWN epoch (DOWN-UP transition), as indicated.Spiking network simulations.We built a network model of leaky integrate-and-fire neurons based in Jercog et al15 , and Barrio et al51 , using the Python-based simulator Brian2 52 . We include n PYR = 4000 excitatory, n INT = 1000 inhibitory and n DSA = 100 neurons with the following connection probability (c): c PYR-PYR = 0.1, c PYR-INT = 0.1, c INT-INT = 0.2, c INT-PYR = 0.3, c PYR-DSA = 931 0.05, c INT-DSA = 0.3, c DSA-PYR = 0.1 and c DSA-INT = 0.1.…”

The Cellular Senescence Stress Response in Post-Mitotic Brain Cells: Cell Survival at the Expense of Tissue Degeneration

“…Various indicators of cell cycle arrest such as cell cycle inhibition and telomere attrition have been discussed for mitotically competent brain cells, for example [ 18 ]. Despite the persistent dogma that neurons permanently withdraw from the cell cycle upon terminal differentiation, numerous studies have demonstrated the expression of cell cycle proteins in post-mitotic neurons, that can give rise to dysfunctional hyperploid cells [ 19 ]. A decrease in telomere length is associated with cell division; notably telomere shortening has been observed in non-replicative neural brain populations in C57BL/6 mice in a cell cycle-independent manner [ 20 ].…”