Neuronal tetraploidy in Alzheimer and aging

Frade, José Marı́a; López-Sánchez, Noelia

doi:10.18632/aging.101312

Cited by 7 publications

(9 citation statements)

References 7 publications

(9 reference statements)

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“…As opposed to senescent somatic cells which arrest proliferation irreversibly, old neurons may do the opposite, reenter the cell cycle, triggering their own demise (Paquola et al, 2016; McConnell et al, 2017; Verheijen et al, 2018). Indeed, the expression of neuronal cell cycle proteins was detected in both healthy seniors and AD patients, suggesting that these molecules are senescence associated (van Leeuwen and Hoozemans, 2015; Frade and López-Sánchez, 2017). In addition, a novel AD postmortem study has linked neuronal senescence with both aggregated tau and neuronal cell cycle reentry, identifying both as age-related traits (Musi et al, 2018).…”

Section: Beta Amyloid: Friend or Foe?mentioning

confidence: 99%

“…Most recent studies have suggested that some neuronal populations reentering the cell cycle do not always undergo cell death but remain in the aneuploid state for the rest of their lives (Frade and López-Sánchez, 2017). For example, loss of the p53 tumor suppressor, a DNA repair protein, was associated with neuronal survival in the aneuploid state (Barrio-Alonso et al, 2018).…”

Section: Beta Amyloid: Friend or Foe?mentioning

confidence: 99%

“…Novel studies in regenerative medicine reported that facilitating cell cycle completion in senescent cardiomyocytes prevented their apoptosis (Anversa and Leri, 2013; Hesse et al, 2017; Locatelli et al, 2018). Helping neurons survive the cell cycle engagement may comprise a therapeutic strategy in AD, but only if aneuploid cells are functional (Frade and López-Sánchez, 2017). Conversely, preventing neurons from engaging the cell cycle, a more straightforward approach, may be accomplished by blocking the nuclear export of Cdk5 or suppressing this protein in the cytosol with Cdk5 blockers or lithium (Zhang et al, 2008; Carvalho et al, 2013).…”

Section: Beta Amyloid: Friend or Foe?mentioning

confidence: 99%

See 2 more Smart Citations

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

Osorio

Kanukuntla

Diaz

et al. 2019

Front. Aging Neurosci.

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The amyloid hypothesis, the assumption that beta-amyloid toxicity is the primary cause of neuronal and synaptic loss, has been the mainstream research concept in Alzheimer's disease for the past two decades. Currently, this model is quietly being replaced by a more holistic, “systemic disease” paradigm which, like the aging process, affects multiple body tissues and organs, including the gut microbiota. It is well-established that inflammation is a hallmark of cellular senescence; however, the infection-senescence link has been less explored. Microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer's disease brains associated with senescent neurons, glia, and endothelial cells. Infectious agents have previously been associated with Alzheimer's disease, but the cause vs. effect issue could not be resolved. A recent study may have settled this debate as it shows that gingipain, a Porphyromonas gingivalis toxin, can be detected not only in Alzheimer's disease but also in the brains of older individuals deceased prior to developing the illness. In this review, we take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. We also surmise that novel Alzheimer's disease findings, including neuronal somatic mosaicism, iron dyshomeostasis, aggressive glial phenotypes, and loss of aerobic glycolysis, can be explained by the infection-senescence model. In addition, we discuss potential cellular senescence targets and therapeutic strategies, including iron chelators, inflammasome inhibitors, senolytic antibiotics, mitophagy inducers, and epigenetic metabolic reprograming.

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Section: Beta Amyloid: Friend or Foe?mentioning

confidence: 99%

Section: Beta Amyloid: Friend or Foe?mentioning

confidence: 99%

Section: Beta Amyloid: Friend or Foe?mentioning

confidence: 99%

See 1 more Smart Citation

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

Osorio

Kanukuntla

Diaz

et al. 2019

Front. Aging Neurosci.

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“…In human and mouse hepatocytes, polyploidization increases with age, injury and infection [25]. In the brain, tetraploid neurons are reported to increase in number with age and in association with degenerative diseases, like Alzheimer’s Disease [35].…”

Section: Ploidy: Why Have Two (Or More) Alleles?mentioning

confidence: 99%

Epigenetic and Cellular Diversity in the Brain through Allele-Specific Effects

Huang

Bennett

Gregg

2018

Trends in Neurosciences

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The benefits of diploidy are considered to involve masking partially recessive mutations and increasing genetic diversity. Here, we review new studies showing evidence for diverse allele-specific expression and epigenetic states in mammalian brain cells, which suggest that diploidy expands the landscape of gene regulatory and expression programs in cells. Allele-specific expression has been thought to be restricted to a few specific classes of genes. However, new studies show novel genomic imprinting effects that are brain-region-, cell-type- and age-dependent. In addition, novel forms of random monoallelic expression that impact many autosomal genes have been described in vitro and in vivo. We discuss the implications for understanding the benefits of diploidy, and the mechanisms shaping brain development, function, and disease.

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“…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 leading to increased DNA levels [i.e., neuronal hyperploidy (NH)] (Frade and Ovejero-Benito, 2015) are known to precede and recapitulate the classical neuropathological signs of AD (Yang et al, 2001;Arendt et al, 2010;Frade and López-Sánchez, 2017). In some cases, NH results in full DNA duplication (i.e., neuronal tetraploidy).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

Self Cite

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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.

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Neuronal tetraploidy in Alzheimer and aging

Cited by 7 publications

References 7 publications

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

Epigenetic and Cellular Diversity in the Brain through Allele-Specific Effects

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

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