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Recommended articles of this week

Published on: 4 Aug 2021 Viewed: 499

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series. This week, we would like to share several latest articles on neurodegenerative disease.

Title: Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis
Authors: Stefano Garofalo, Germana Cocozza, Alessandra Porzia, Maurizio Inghilleri, Marcello Raspa, Ferdinando Scavizzi, Eleonora Aronica, Giovanni Bernardini, Ling Peng, Richard M. Ransohoff, Angela Santoni, Cristina Limatola
Type: Article from Nature Communications
Abstract:
In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1G93A, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43A315T. NK cells are neurotoxic to hSOD1G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3+/Treg cell infiltration in the spinal cord of hSOD1G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.
Access this article: https://doi.org/10.1038/s41467-020-15644-8


Title: Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases
Authors: Doortje W. Dekens, Ulrich L. M. Eisel, Leonie Gouweleeuw, Regien G. Schoemaker, Peter P. De Deyn, Petrus J.W.Naudé
Type: Review of Ageing Research Reviews
Highlights:
• Lcn2 increases with age and risk factors for age-related brain diseases.
• Peripheral and brain Lcn2 levels are increased in brain disorders.
• Lcn2 is involved in the pathophysiological processes of age-related brain diseases.
• The effects of Lcn2 in the brain depends on the neuropathological state.
• Lcn2 is a key constituent in aging and age-related brain diseases.
Abstract:
Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer’s disease, Parkinson’s disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases.
Access this article: https://doi.org/10.1016/j.arr.2021.101414


Title: Targeting immune dysfunction in aging
Authors: Simone Borgoni, Ksenia S. Kudryashova, Ksenia Burka, João Pedrode Magalhães
Type: Review of Ageing Research Reviews
Highlights:
• The immune system becomes highly dysfunctional during aging and new anti-aging therapeutic approaches targeting the immune system are being proposed at a growing pace, with many of them showing promising pre-clinical results.
• Due to its interconnection with all other systems in the body, its relevance for homeostasis maintenance and the primary role in fighting infections and cancer, the immune system represents the ideal target to comprehensively address many hallmarks of aging.
• Successful immune targeting approaches are directed either against specific cell types (hematopoietic stem cells, T cells, macrophages) or processes (immune metabolism, immune senescence).
• Current promising immune-targeting strategies involve: rejuvenation of aged immune tissues or cells, immunosuppressive strategies to tune down dysregulated populations that promote inflammaging and stimulatory strategies to re-activate, eliminate, or replace senescent cells.
• Targeting multiple components of the immune system at once requires an extremely balanced approach to avoid undesired side effects.
Abstract:
Human aging is a multifactorial phenomenon that affects numerous organ systems and cellular processes, with the immune system being one of the most dysregulated. Immunosenescence, the gradual deterioration of the immune system, and inflammaging, a chronic inflammatory state that persists in the elderly, are among the plethora of immune changes that occur during aging. Almost all populations of immune cells change with age in terms of numbers and/or activity. These alterations are in general highly detrimental, resulting in an increased susceptibility to infections, reduced healing abilities, and altered homeostasis that promote the emergence of age-associated diseases such as cancer, diabetes, and other diseases associated with inflammation. Thanks to recent developments, several strategies have been proposed to target central immunological processes or specific immune subpopulations affected by aging. These therapeutic approaches could soon be applied in the clinic to slow down or even reverse specific age-induced immune changes in order to rejuvenate the immune system and prevent or reduce the impact of various diseases. Due to its systemic nature and interconnection with all the other systems in the body, the immune system is an attractive target for aging intervention because relatively targeted modifications to a small set of cells have the potential to improve the health of multiple organ systems. Therefore, anti-aging immune targeting therapies could represent a potent approach for improving healthspan. Here, we review aging changes in the major components of the immune system, we summarize the current immune-targeting therapeutic approaches in the context of aging and discuss the future directions in the field of immune rejuvenation.
Access this article: https://doi.org/10.1016/j.arr.2021.101410


Title: Western diet as a trigger of Alzheimer’s disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration
Authors: Angelika Więckowska-Gacek, Anna Mietelska-Porowska, Małgorzata Wydrych, UrszulaWojda
Type: Review of Ageing Research Reviews
Highlights:
• Western diet (WD) can accelerate and enhance inflammaging and induction of Alzheimer’s disease (AD).
• WD-induced obesity, metabolic disorders and gut microbiota dysbiosis can lead to AD.
• WD-induced metabolic and systemic inflammation impair blood-brain barrier.
• WD drives neuroinflammation, amyloid and tau pathology, and memory impairment.
• Dietary manipulations hold promise for AD prevention and support in therapy.
Abstract:
An excess of saturated fatty acids and simple sugars in the diet is a known environmental risk factor of Alzheimer's disease (AD) but the holistic view of the interacting processes through which such diet may contribute to AD pathogenesis is missing. We addressed this need through extensive analysis of published studies investigating the effects of western diet (WD) on AD development in humans and laboratory animals. We reviewed WD-induced systemic alterations comprising metabolic changes, induction of obesity and adipose tissue inflammation, gut microbiota dysbiosis and acceleration of systemic low-grade inflammation. Next we provide an overview of the evidence demonstrating that WD-associated systemic alterations drive impairment of the blood-brain barrier (BBB) and development of neuroinflammation paralleled by accumulation of toxic amyloid. Later these changes are followed by dysfunction of synaptic transmission, neurodegeneration and finally memory and cognitive impairment. We conclude that WD can trigger AD by acceleration of inflammaging, and that BBB impairment induced by metabolic and systemic inflammation play the central role in this process. Moreover, the concurrence of neuroinflammation and Aβ dyshomeostasis, which by reciprocal interactions drive the vicious cycle of neurodegeneration, contradicts Aβ as the primary trigger of AD. Given that in 2019 the World Health Organization recommended focusing on modifiable risk factors in AD prevention, this overview of the sequential, complex pathomechanisms initiated by WD, which can lead from peripheral disturbances to neurodegeneration, can support future prevention strategies.
Graphical abstract:

Access this article: https://doi.org/10.1016/j.arr.2021.101397


Title: Can healthy lifestyle reduce disease progression of Alzheimer’s during a global pandemic of COVID-19?
Authors: Albin John, Kiran Ali, Harrison Marsh, P. Hemachandra Reddy
Type: Review of Ageing Research Reviews
Highlights:
• The novel coronavirus disease 2019 (COVID-19) still pandemic and threat to humans.
• Elderly individuals with multiple comorbidities are susceptible to COVID-19.
• Multiple factors such genetics, metabolism, and lifestyle factors are involved in both COVID-19 and Alzheimer’s disease.
• Healthy lifestyle factors reduce and/or combat COVID-19 now and in the future.
Abstract:
The novel coronavirus disease 2019 (COVID-19) has pushed the medical system to its breaking point. While the virus does not discriminate, the elderly and those with comorbidities, including hypertension severe obesity, diabetes mellitus, coronary disease, pneumonia and dementia, are at a greater risk for adverse outcomes due to COVID-19. While many people navigate their new normal, the question of what the long-lasting effects of the pandemic may be, lingers. To investigate how vulnerable populations are affected by the pandemic, we focused on Alzheimer’s disease, a vector to understanding how the virus has impacted AD progression and risk via aging. By assessing the effect of COVID-19 on AD patients, we explore genetics, metabolism, and lifestyle factors in both COVID-19 and Alzheimer’s disease that can work synergistically to precipitate adverse outcomes. This article also discusses how age-related conditions and/or age-related comorbidities susceptible to COVID-19. We also discuss possible healthy lifestyle factors reduce and/or combat COVID-19 now and in the future.
Access this article: https://doi.org/10.1016/j.arr.2021.101406


Title: The neuromicrobiology of Parkinson’s disease: A unifying theory
Authors: Mario F. Munoz-Pinto, Nuno Empadinhas, Sandra M. Cardoso
Type: Review of Ageing Research Reviews
Highlights:
• Parkinson’s disease (PD) is a common progressive neurodegenerative disease with many potential aetiologies.
• Bacteria are the new players involved in PD onset and progression.
• Gut microbiome modulates the gut-brain axis by potentiating alpha-synuclein (ASYN) misfolding inducing prion-like PD.
• Gut microbiome modulates the gut-brain axis inducing gut and brain inflammation leading to immune-like PD.
• Gut microbiome modulates the gut-brain axis trough gut microbiota metabolites, such as SCFAs.
Abstract:
Recent evidence confirms that PD is indeed a multifactorial disease with different aetiologies and prodromal symptomatology that likely depend on the initial trigger. New players with important roles as triggers, facilitators and aggravators of the PD neurodegenerative process have re-emerged in the last few years, the microbes. Having evolved in association with humans for ages, microbes and their products are now seen as fundamental regulators of human physiology with disturbances in their balance being increasingly accepted to have a relevant impact on the progression of disease in general and on PD in particular. In this review, we comprehensively address early studies that have directly or indirectly linked bacteria or other infectious agents to the onset and progression of PD, from the earliest suspects to the most recent culprits, the gut microbiota. The quest for effective treatments to arrest PD progression must inevitably address the different interactions between microbiota and human cells, and naturally consider the gut-brain axis. The comprehensive characterization of such mechanisms will help design innovative bacteriotherapeutic approaches to selectively shape the gut microbiota profile ultimately to halt PD progression. The present review describes our current understanding of the role of microorganisms and their endosymbiotic relatives, the mitochondria, in inducing, facilitating, or aggravating PD pathogenesis.
Access this article: https://doi.org/10.1016/j.arr.2021.101396


Title: Interspecific interactions that affect ageing: Age-distorters manipulate host ageing to their own evolutionary benefits
Authors: Jérôme Teulière, Charles Bernard, Eric Bapteste
Type: Review of Ageing Research Reviews
Highlights:
• Genetic causes of cell/organismal ageing external to a focal species may be neglected.
• Many age-distorters may interfere with ageing in other species for their own interest.
• Co-evolution/arms races with age-distorters would affect genetics of ageing evolution.
• Genes in viruses, parasites or symbionts may often turn hosts into disposable soma.
• Modelling age-distorters can expand the scope of major non-adaptive theories of ageing.
Abstract:
Genetic causes for ageing are traditionally investigated within a species. Yet, the lifecycles of many organisms intersect. Additional evolutionary and genetic causes of ageing, external to a focal species/organism, may thus be overlooked. Here, we introduce the phrase and concept of age-distorters and its evidence. Age-distorters carry ageing interfering genes, used to manipulate the biological age of other entities upon which the reproduction of age-distorters relies, e.g. age-distorters bias the reproduction/maintenance trade-offs of cells/organisms for their own evolutionary interests. Candidate age-distorters include viruses, parasites and symbionts, operating through specific, genetically encoded interferences resulting from co-evolution and arms race between manipulative non-kins and manipulable species. This interference results in organismal ageing when age-distorters prompt manipulated organisms to favor their reproduction at the expense of their maintenance, turning these hosts into expanded disposable soma. By relying on reproduction/maintenance trade-offs affecting disposable entities, which are left ageing to the reproductive benefit of other physically connected lineages with conflicting evolutionary interests, the concept of age-distorters expands the logic of the Disposable Soma theory beyond species with fixed germen/soma distinctions. Moreover, acknowledging age-distorters as external sources of mutation accumulation and antagonistic pleiotropic genes expands the scope of the mutation accumulation and of the antagonistic pleiotropy theories.
Access this article: https://doi.org/10.1016/j.arr.2021.101375



Title: Mitochondria: Their relevance during oocyte ageing
Authors: Jiskavan der Reest, Gustavo Nardini Cecchino, Marcia C. Haigis, Paweł Kordowitzki
Type: Review of Ageing Research Reviews
Highlights:
• In women, the reproductive system ages early in life and could represent a model to study ageing in general.
• Mitochondria integrate processes essential for oocyte function, such as energy production, biosynthesis, and redox homeostasis.
• Dysregulation of mitochondrial processes have been consistently reported in ageing and age-related diseases.
• Mitochondrial dysfunction is a key factor responsible for chromosomal anomalies during the meiotic divisions of mammalian oocytes.
• Several therapeutic strategies have been developed to halt, delay, or partially reverse oocyte ageing.
Abstract:
The oocyte is recognised as the largest cell in mammalian species and other multicellular organisms. Mitochondria represent a high proportion of the cytoplasm in oocytes and mitochondrial architecture is different in oocytes than in somatic cells, characterised by a rounder appearance and fragmented network. Although the number of mitochondria per oocyte is higher than in any other mammalian cell, their number and activity decrease with advancing age. Mitochondria integrate numerous processes essential for cellular function, such as metabolic processes related to energy production, biosynthesis, and waste removal, as well as Ca2+ signalling and reactive oxygen species (ROS) homeostasis. Further, mitochondria are responsible for the cellular adaptation to different types of stressors such as oxidative stress or DNA damage. When these stressors outstrip the adaptive capacity of mitochondria to restore homeostasis, it leads to mitochondrial dysfunction. Decades of studies indicate that mitochondrial function is multifaceted, which is reflected in the oocyte, where mitochondria support numerous processes during oocyte maturation, fertilization, and early embryonic development. Dysregulation of mitochondrial processes has been consistently reported in ageing and age-related diseases. In this review, we describe the functions of mitochondria as bioenergetic powerhouses and signal transducers in oocytes, how dysfunction of mitochondrial processes contributes to reproductive ageing, and whether mitochondria could be targeted to promote oocyte rejuvenation.
Access this article: https://doi.org/10.1016/j.arr.2021.101378



Title: Gene targeting techniques for Huntington’s disease
Authors: Eric Fields, Erik Vaughan, Deepika Tripu, Isabelle Lim, Katherine Shrout, Jessica Conway, Nicole Salib, Yubin Lee, Akash Dhamsania, Michael Jacobsen, Ashley Woo, Huijing Xue, Kan Cao
Type: Review of Ageing Research Reviews
Highlights:
• The exact function of human huntingtin protein is still uncertain, but evidence for its roles in key functions is increasing.
• Targeted efforts to downregulate the mutant huntingtin protein in both allele-specific and non-allele specific ways have been explored.
• Prime editing technology provides a potential new avenue for regulating mutant huntingtin expression.
Abstract:
Huntington’s disease (HD) is an autosomal neurodegenerative disorder caused by extended trinucleotide CAG repetition in the HTT gene. Wild-type huntingtin protein (HTT) is essential, involved in a variety of crucial cellular functions such as vesicle transportation, cell division, transcription regulation, autophagy, and tissue maintenance. The mutant HTT (mHTT) proteins in the body interfere with HTT’s normal cellular functions and cause additional detrimental effects. In this review, we discuss multiple approaches targeting DNA and RNA to reduce mHTT expression. These approaches are categorized into non-allele-specific silencing and allele-specific-silencing using Single Nucleotide Polymorphisms (SNPs) and haplogroup analysis. Additionally, this review discusses a potential application of recent CRISPR prime editing technology in targeting HD.
Access this article: https://doi.org/10.1016/j.arr.2021.101385

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