Reference
Saez-Atienzar, S., Masliah, E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat Rev Neurosci 21, 433–444 (2020).
At a glance
The article is a scientific literature review that highlights the tight connection between aging, cellular senescence and neurodegenerative diseases. In particular, the authors point out the correlation between cellular senescence and Alzheimer’s disease. Cellular senescence might have a key role in the progression of Alzheimer’s disease, through several protein aggregation-related mechanisms and other mechanisms related to genetic risk and myelin disruption in the brain which occurs with aging. Despite this evidence, there is still a debate as to whether cellular senescence is the cause or the effect of neurodegeneration. This relationship must be further investigated, especially because preclinical data suggests that senolytics (drugs that selectively kill senescent cells) are a very promising therapy. Senescent cells might be a potential target for treating or preventing Alzheimer’s disease as well as other neurodegenerative diseases.
What is already known
Aging is the main risk factor for dementia-related neurodegenerative diseases such as Alzheimer’s disease. Cellular senescence is considered a hallmark of aging: it is a dynamic and multistage process in which cells permanently arrest proliferation. From the earliest stage, and especially in late senescence, cells acquire a particular phenotype, known as SASP, in which they produce pro-inflammatory molecules. These molecules have an autocrine and paracrine action, causing even neighbouring cells to enter into senescence. The SASP signal also activates an immune response that seeks to remove senescent cells. However, with aging and the presence of chronic stress, this mechanism does not work well, causing senescent cells to accumulate in the brain, which can lead to chronic inflammation. Senescence is inevitable in aging, as a consequence of damage accumulation throughout an individual’s lifetime. Senescent cells have been found in several tissues of aged individuals as well as in individuals with premature aging syndromes. In fact, many in vivo studies suggest that cellular senescence might induce the aging process, and more and more evidence underlines the key role of cellular senescence in neurodegenerative diseases. The aim of this paper is to review the scientific literature in order to find potential senescence-related mechanisms that have a role in the onset and progression of neurodegenerative diseases.
Main results
Upregulation of cell cycle regulators and senescence markers (CDK4, its inhibitor p16 and beta-galactosidase enzyme) have been found in a very large amount of brain cell types associated with Alzheimer’s disease. The authors here present two different mechanisms through which cellular senescence might play a key role in this disease: one of these depends on toxic protein accumulation, which is the main hallmark of the disease (intracellular protein tau-containing neurofibrillary tangles and extracellular beta-amyloid plaques), while the other one might involve protein aggregation-independent processes. Evidence suggests that protein aggregation-related toxicity induces cellular senescence and inflammation in the brain:
• In vitro human and murine data suggest that beta-amyloid deposition could be a trigger of senescence both in astrocyte and in microglia. Moreover, a recent study demonstrated that beta-amyloid accumulation induces cellular senescence in another kind of brain cell, oligodendrocyte progenitor cells;
• The formation of tau-containing neurofibrillary tangles in human and murine neuron cells triggers a cascade of metabolic modifications, gene expression alterations and induction of DNA damage that are highly correlated to senescence. Protein tau aggregation might induce senescence in neurons as a stress response, probably by regulating genes Cdk1a and Cdk2a. These genes, though, are the same ones that stimulate the SASP phenotype, provoking an inflammatory state that might worsen neurodegeneration.On the other hand, several studies highlight that senescent brain cells can induce protein-dependent toxicity, with consequent inflammation and neurodegeneration. This suggests that senescence might play a key role in the onset and progression of the disease:
• Mouse models of neurodegenerative disease showed that the removal of senescent astrocytes and microglia cells diminished neurofibrillary tangles, consequently improving cognitive decline; • Another study showed that treating transgenic mice – those prone to accumulating the beta amyloid precursor protein and exhibiting symptoms of early-onset Alzheimer’s disease – with dasatinib and quercetin (FDA-approved senolytics, drugs that selectively kill senescent cells) reported a reduction of amyloid plaques and improvement in memory and learning;
• Several post-mortem brain analyses of patients with neurodegenerative diseases showed that senescent microglia cells were present in brain areas where toxic protein accumulation was expected to develop but had not yet occurred, suggesting that cellular senescence might precede this event. Besides this evidence, the study authors present several mechanisms, independent of tau protein and beta amyloid aggregation, that might contribute to the accumulation of senescent cells in Alzheimer’s disease:
• Thanks to genome-wide association studies, it was found that patients with Alzheimer’s disease possess a genetic risk associated with gene variants known to be involved in cellular senescence. Individuals more at risk of developing Alzheimer’s disease, therefore, are the same as those more susceptible to cellular senescence activation, and to inflammation;
• MRI studies have shown that, with aging, the amount of myelin in the brain decreases. In fact, loss of myelin has been associated with neurodegenerative diseases. The amount of myelin depends on the activity of oligodendrocytes (cells that produce this substance) and that of microglia (cells that have to eliminate cellular debris). A myelin debris overload, which is common with aging, might induce cellular senescence in microglia, leading to a chronic inflammation that causes an impairment of all of the brain cells.
Study limitations
Even though much evidence has been reported here, it is still not clear whether cellular senescence might be the cause or the effect of Alzheimer’s disease. Furthermore, some of the reported studies were animal models of early aging, a condition that itself is a source of stress on the body, so the conclusions drawn about cellular senescence could be called into question. Moreover, in the study there is a paragraph about senolytics, drugs that selectively kill senescent cells, that are now under clinical trial as a promising therapy to prevent, delay or treat dementia symptoms. That said, unknown adverse effects might occur by using these drugs because senescence is a natural process, and the elimination of senescent cells could impair mechanisms such as wound healing.
What are the prospects
A next step in shedding light on the causal relationship between cellular senescence and Alzheimer’s disease would be to find genes involved in the senescence pathway in the genetic loci associated with the disease. An interesting approach could be evaluating, through genome-wide studies, how the variations of these genes could influence the different outcomes of the disease. Furthermore, functional genomic studies could clarify whether cellular senescence is the cause or the effect of neurodegeneration.
By Chiara Di Lucente
