Activation of autophagy ameliorates age-related neurogenesis decline and neurodysfunction in adult mice

Abstract Adult neurogenesis is the ongoing generation of functional new neurons from neural progenitor cells (NPCs) in the mammalian brain. However, this process declines with aging, which is implicated in the recession of brain function and neurodegeneration. Understanding the mechanism of adult neurogenesis and stimulating it will benefit the mitigation of neurodegenerative diseases. Autophagy, a highly conserved process of cellular degradation, is essential for maintaining cellular homeostasis and normal function. Whether and how autophagy affects adult neurogenesis remains poorly understood. In present study, we revealed a close connection between impaired autophagy and adult neurogenetic decline. Expression of autophagy-related genes and autophagic activity were significantly declined in the middle-aged subventricular/subgranular zone (SVZ/SGZ) homogenates and cultured NPCs, and inhibiting autophagy by siRNA interference resulted in impaired pluripotency of NPCs. Conversely, stimulating autophagy by rapamycin not only revitalized the viability and pluripotency of middle-aged NPCs, but also facilitated the neurogenesis in middle-aged SVZ/SGZ. More importantly, autophagic activation by rapamycin also ameliorated the olfactory sensitivity and cognitional capacities in middle-aged mice. Taken together, our results reveal that compromised autophagy is involved in the decline of adult neurogenesis, which could be reversed by autophagy activation. It also shed light on the regulation of adult neurogenesis and paves the way for developing therapeutic strategy for aging and neurodegenerative diseases.

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Mercury Toxicity and Neurogenesis in the Mammalian Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22147520 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7520

Author(s):

Louise C. Abbott ◽

Fikru Nigussie

Keyword(s):

Neural Networks ◽

Progenitor Cells ◽

Adult Neurogenesis ◽

Neural Progenitor Cells ◽

Mammalian Brain ◽

Mercury Toxicity ◽

Embryonic Neurogenesis ◽

Programmed Death ◽

Final Integration ◽

Developing Neurons

The mammalian brain is formed from billions of cells that include a wide array of neuronal and glial subtypes. Neural progenitor cells give rise to the vast majority of these cells during embryonic, fetal, and early postnatal developmental periods. The process of embryonic neurogenesis includes proliferation, differentiation, migration, the programmed death of some newly formed cells, and the final integration of differentiated neurons into neural networks. Adult neurogenesis also occurs in the mammalian brain, but adult neurogenesis is beyond the scope of this review. Developing embryonic neurons are particularly susceptible to neurotoxicants and especially mercury toxicity. This review focused on observations concerning how mercury, and in particular, methylmercury, affects neurogenesis in the developing mammalian brain. We summarized information on models used to study developmental mercury toxicity, theories of pathogenesis, and treatments that could be used to reduce the toxic effects of mercury on developing neurons.

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Abstract 123: Age-Related Diminishment of the Subventricular Zone Cytogenic Response and Its Contributions to Motor Recovery After Cortical Infarcts

Stroke ◽

10.1161/str.51.suppl_1.123 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Michael R Williamson ◽

Stephanie Le ◽

Ronald L Franzen ◽

Michael R Drew ◽

Theresa A Jones

Keyword(s):

Young Adult ◽

Subventricular Zone ◽

Motor Recovery ◽

Lineage Tracing ◽

Stem Cell Markers ◽

Middle Aged ◽

Reaching Task ◽

Aged Mice ◽

Adult Mice ◽

Age Related

Stroke increases proliferation within the subventricular zone (SVZ) cytogenic niche and causes subsequent migration of newborn cells towards the site of injury. We investigated the functional consequences of age-related blunting of the SVZ cytogenic response to ischemia. We found that there was a marked reduction in proliferation and neural stem cell markers within the SVZ of middle aged (aged 12-16 months) versus young adult (aged 3-5 months) mice in the intact brain and after photothrombotic infarcts in motor cortex. Using an inducible, heritable lineage tracing system (Nestin-CreER T2 :: Ai14 mice) to quantify SVZ-derived neural precursor cells (NPCs) that migrated towards the infarct, we found that there was a considerable age-related reduction in the number of NPCs in peri-infarct cortex. These findings indicate a marked diminishment of SVZ NPC proliferation and migration after focal ischemia by middle age. Next, we assessed the contributions of the SVZ cytogenic response to recovery of skilled motor function. We used glial fibrillary acidic protein-thymidine kinase mice to conditionally ablate NPCs with ganciclovir administration. In young adult mice, NPC ablation significantly impaired recovery of motor performance on the single seed reaching task after motor cortical infarcts. By contrast, NPC ablation did not affect motor recovery in middle aged mice. Importantly, the magnitude of recovery was less in middle aged mice—regardless of NPC ablation—than in control young adult mice. Middle aged mice recovered similarly to young adult mice lacking NPCs. These results indicate that SVZ cytogenesis contributes to functional improvements after cortical infarcts and that the diminishment of the cytogenic response with age may be implicated in age-related worsening of outcome after stroke. Restoration of SVZ cytogenesis in aged animals might improve behavioral recovery.

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Healthy Brain Aging Modifies Microglial Calcium Signaling In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms20030589 ◽

2019 ◽

Vol 20 (3) ◽

pp. 589 ◽

Cited By ~ 10

Author(s):

Maria Olmedillas del Moral ◽

Nithi Asavapanumas ◽

Néstor Uzcátegui ◽

Olga Garaschuk

Keyword(s):

Young Adult ◽

Brain Aging ◽

Critical Role ◽

Low Grade ◽

Middle Aged ◽

Senescent Phenotype ◽

Adult Mice ◽

Age Related ◽

Old Mice

Brain aging is characterized by a chronic, low-grade inflammatory state, promoting deficits in cognition and the development of age-related neurodegenerative diseases. Malfunction of microglia, the brain-resident immune cells, was suggested to play a critical role in neuroinflammation, but the mechanisms underlying this malfunctional phenotype remain unclear. Specifically, the age-related changes in microglial Ca2+ signaling, known to be linked to its executive functions, are not well understood. Here, using in vivo two-photon imaging, we characterize intracellular Ca2+ signaling and process extension of cortical microglia in young adult (2–4-month-old), middle-aged (9–11-month-old), and old (18–21-month-old) mice. Our data revealed a complex and nonlinear dependency of the properties of intracellular Ca2+ signals on an animal’s age. While the fraction of cells displaying spontaneous Ca2+ transients progressively increased with age, the frequencies and durations of the spontaneous Ca2+ transients followed a bell-shaped relationship, with the most frequent and largest Ca2+ transients seen in middle-aged mice. Moreover, in old mice microglial processes extending toward an ATP source moved faster but in a more disorganized manner, compared to young adult mice. Altogether, these findings identify two distinct phenotypes of aging microglia: a reactive phenotype, abundantly present in middle-aged animals, and a dysfunctional/senescent phenotype ubiquitous in old mice.

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New neurons in old brains: A cautionary tale for the analysis of neurogenesis in post-mortem tissue.

10.1101/2021.11.12.468443 ◽

2021 ◽

Author(s):

Dylan J Terstege ◽

Kwaku Addo-Osafo ◽

Gordon Campbell Teskey ◽

Jonathan R Epp

Keyword(s):

Adult Neurogenesis ◽

Mammalian Species ◽

Adult Brain ◽

Mammalian Brain ◽

Tissue Fixation ◽

Post Mortem ◽

Biological Difference ◽

High Profile ◽

Age Related ◽

Morphological Detail

Adult neurogenesis has primarily been examined in two key regions in the mammalian brain, the subgranular zone of the hippocampus and the subventricular zone. The proliferation and integration of newly generated neurons has been observed widely in adult mammalian species including the human hippocampus. Recent high-profile studies have suggested however, that this process is considerably reduced in humans, occurring in children but declining rapidly and nearly completely in the adult brain. In comparison, rodent studies also show age-related decline but a greater degree of proliferation of new neurons in adult animals. Here, we examine whether differences in tissue fixation, rather than biological difference in human versus rodent studies might account for the diminished levels of neurogenesis sometimes observed in the human brain. To do so we analyzed neurogenesis in the hippocampus of rats that were either perfusion-fixed or the brains extracted and immersion-fixed at various post-mortem intervals. We observed an interaction between animal age and the time delay between death and tissue fixation. While similar levels of neurogenesis were observed in young rats regardless of fixation, older rats had significantly fewer labeled neurons when fixation was not immediate. Furthermore, the morphological detail of the labeled neurons was significantly reduced in the delayed fixation conditions at all ages. This study highlights critical concerns that must be considered when using post-mortem tissue to quantify adult neurogenesis.

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Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

10.1101/2021.12.26.473589 ◽

2021 ◽

Author(s):

Jeffrey R Atkinson ◽

Andrew D Jerome ◽

Andrew R Sas ◽

Ashley Munie ◽

William David Arnold ◽

...

Keyword(s):

Adoptive Transfer ◽

Microglial Activation ◽

Demyelinating Disease ◽

Clinical Course ◽

Dominant Role ◽

Biological Aging ◽

Middle Aged ◽

Adult Mice ◽

Age Related ◽

Bone Marrow Chimeras

Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing remitting MS (RRMS) typically presents in the third or fourth decade, while the mean age of presentation of progressive MS (pMS) is 45 years old. Here we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, is more severe, and less like to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils are more abundant, while B cells are relatively sparse, in central nervous system (CNS) infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrate that radio-resistant, non-hematopoietic cells play a dominant role in shaping age-related features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of pMS, EAE in middle-aged adoptive transfer recipients is characterized by widespread microglial activation. Microglia from older mice express a distinctive transcriptomic profile, suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.

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Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

Antioxidants ◽

10.3390/antiox9111095 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1095

Author(s):

Ana Gámez-Valero ◽

Anna Guisado-Corcoll ◽

Marina Herrero-Lorenzo ◽

Maria Solaguren-Beascoa ◽

Eulàlia Martí

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Nervous System ◽

Neurodegenerative Diseases ◽

Reactive Oxygen ◽

Cell Types ◽

Normal Function ◽

Brain Cell ◽

Oxygen Species ◽

Age Related

Oxidative stress (OS) results from an imbalance between the production of reactive oxygen species and the cellular antioxidant capacity. OS plays a central role in neurodegenerative diseases, where the progressive accumulation of reactive oxygen species induces mitochondrial dysfunction, protein aggregation and inflammation. Regulatory non-protein-coding RNAs (ncRNAs) are essential transcriptional and post-transcriptional gene expression controllers, showing a highly regulated expression in space (cell types), time (developmental and ageing processes) and response to specific stimuli. These dynamic changes shape signaling pathways that are critical for the developmental processes of the nervous system and brain cell homeostasis. Diverse classes of ncRNAs have been involved in the cell response to OS and have been targeted in therapeutic designs. The perturbed expression of ncRNAs has been shown in human neurodegenerative diseases, with these changes contributing to pathogenic mechanisms, including OS and associated toxicity. In the present review, we summarize existing literature linking OS, neurodegeneration and ncRNA function. We provide evidences for the central role of OS in age-related neurodegenerative conditions, recapitulating the main types of regulatory ncRNAs with roles in the normal function of the nervous system and summarizing up-to-date information on ncRNA deregulation with a direct impact on OS associated with major neurodegenerative conditions.

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Effect of chronic intranasal administration of α-synuclein oligomers on motor activity and anxiety in adult and middle-aged mice

Nauchno-prakticheskii zhurnal «Patogenez» ◽

10.25557/2310-0435.2019.03.34-40 ◽

2019 ◽

pp. 34-40

Author(s):

О.А. Соловьева ◽

М.А. Грудень ◽

В.В. Шерстнев

Keyword(s):

Motor Activity ◽

Motor Behavior ◽

Lewy Body Dementia ◽

Chronic Administration ◽

Middle Aged ◽

Aged Mice ◽

Adult Mice ◽

Age Related ◽

Plus Maze ◽

Age Dependent

К числу наименее экспериментально изученных аспектов патогенеза α-синуклеинопатий (основными представителями которых являются болезнь Паркинсона и деменция с тельцами Леви) относятся возрастные особенности влияния амилоидогенных форм α-синуклеина, образующихся в результате его гиперэкспрессии и мисфолдинга, на поведение и физиологические функции млекопитающих. Цель исследования состояла в изучении влияния олигомеров α-синуклеина на двигательную активность и тревожность взрослых и стареющих мышей. Материалы и методы. Опыты проводили на 6- и 12-месячных самцах мышей C57Bl/6, которым на протяжении 14 дней один раз в сутки вводили раствор олигомеров α-синуклеина (суммарная доза 0,48 мг/кг) или физиологический раствор. Для оценки общей двигательной активности и тревожности использовали тесты «Открытое поле» и «Приподнятый крестообразный лабиринт». Результаты. Обнаружено, что олигомеры α-синуклеина при хроническом введении вызывают у взрослых мышей возрастание тревожности без общих двигательных нарушений, в то время как у стареющих мышей - нарушение двигательной активности (снижение средней скорости и длины пройденного пути) и рост тревожности. Выводы. Полученные данные свидетельствуют о возраст зависимом характере поведенческих эффектов олигомеров α-синуклеина в условиях хронического интраназального введения. Among the least experimentally studied aspects of the pathogenesis of α- synucleinopathies (major representatives, Parkinson`s disease and Lewy body dementia) are age-related effects of amyloidogenic α-synuclein species resulting from overexpression and misfolding on mammalian behavior and physiological functions. The aim of this study was to evaluate effects of α-synuclein oligomers on motor behavior and anxiety in adult and middle-aged mice. Methods. Experiments were performed on 6- and 12-month-old male C57Bl/6 mice. A solution of α-synuclein oligomers or saline was administered once a day for 14 days (total dose, 0.48 mg/kg). To evaluate the overall motor activity and anxiety, the open field and elevated plus maze tests were used. Results. Chronic administration of α-synuclein oligomers to adult mice increased anxiety without overall motor disorders while middle-aged mice demonstrated both changes in their motor activity (decreases in average speed and path length) and increased anxiety. Conclusions. The study showed that the behavioral effects of α-synuclein oligomers administered chronically, intranasally were age-dependent.

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The piRNA pathway sustains adult neurogenesis by repressing protein synthesis

10.1101/2020.09.15.297739 ◽

2020 ◽

Author(s):

C. Gasperini ◽

R. Pelizzoli ◽

A. Lo Van ◽

D. Mangoni ◽

R.M. Cossu ◽

...

Keyword(s):

Protein Synthesis ◽

Adult Neurogenesis ◽

Neural Progenitor Cells ◽

Brain Plasticity ◽

Mammalian Brain ◽

Loss Of Function ◽

Transfer Rnas ◽

Pirna Pathway

AbstractIn specific niches of the adult mammalian brain, neural progenitor cells (aNPCs) ensure lifelong neurogenesis. Proper regulation of this process entails important implications for brain plasticity and health. We report that Piwil2 (Mili) and PIWI-interacting RNAs (piRNAs) are abundantly expressed in aNPCs but depleted in their progeny in the adult mouse hippocampus. Loss of function of the piRNA pathway in aNPCs inhibited neurogenesis and increased reactive gliogenesis in vivo and in vitro. PiRNA pathway depletion in cultured aNPCs increased levels of 5S ribosomal RNA, transfer RNAs and mRNAs encoding regulators of translation, resulting in higher polyribosome density and protein synthesis upon differentiation. We propose that the piRNA pathway sustains adult neurogenesis by repressing translation in aNPCs.One sentence summaryThe piRNA pathway is enriched in neural precursors and essential for appropriate neurogenesis by modulating translation

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Autophagy and ageing: implications for age-related neurodegenerative diseases

Essays in Biochemistry ◽

10.1042/bse0550119 ◽

2013 ◽

Vol 55 ◽

pp. 119-131 ◽

Cited By ~ 37

Author(s):

Bernadette Carroll ◽

Graeme Hewitt ◽

Viktor I. Korolchuk

Keyword(s):

Neurodegenerative Diseases ◽

Energy Availability ◽

Future Studies ◽

Intracellular Degradation ◽

Age Related ◽

Autophagy Induction ◽

Social Importance ◽

Cellular Dysfunction ◽

Autophagy Activity ◽

Intense Research

Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our ‘ageing’ world.

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Minerals Intake Distributions in a Large Sample of Iranian at-Risk Population Using the National Cancer Institute Method: Do They Meet Their Requirements?

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000232 ◽

2015 ◽

Vol 85 (3-4) ◽

pp. 129-144 ◽

Cited By ~ 3

Author(s):

Zahra Heidari ◽

Awat Feizi ◽

Leila Azadbakht ◽

Nizal Sarrafzadegan

Keyword(s):

At Risk ◽

National Cancer Institute ◽

Population Based ◽

Cross Sectional Study ◽

Normal Function ◽

Dietary Intakes ◽

Middle Aged ◽

Cross Sectional ◽

Nutritional Interventions ◽

High Prevalence

Abstract. Background: Minerals are required for the body’s normal function. Aim: The current study assessed the intake distribution of minerals and estimated the prevalence of inadequacy and excess among a representative sample of healthy middle aged and elderly Iranian people. Methods: In this cross-sectional study, the second follow up to the Isfahan Cohort Study (ICS), 1922 generally healthy people aged 40 and older were investigated. Dietary intakes were collected using 24 hour recalls and two or more consecutive food records. Distribution of minerals intake was estimated using traditional (averaging dietary intake days) and National Cancer Institute (NCI) methods, and the results obtained from the two methods, were compared. The prevalence of minerals intake inadequacy or excess was estimated using the estimated average requirement (EAR) cut-point method, the probability approach and the tolerable upper intake levels (UL). Results: There were remarkable differences between values obtained using traditional and NCI methods, particularly in the lower and upper percentiles of the estimated intake distributions. A high prevalence of inadequacy of magnesium (50 - 100 %), calcium (21 - 93 %) and zinc (30 - 55 % for males > 50 years) was observed. Significant gender differences were found regarding inadequate intakes of calcium (21 - 76 % for males vs. 45 - 93 % for females), magnesium (92 % vs. 100 %), iron (0 vs. 15 % for age group 40 - 50 years) and zinc (29 - 55 % vs. 0 %) (all; p < 0.05). Conclusion: Severely imbalanced intakes of magnesium, calcium and zinc were observed among the middle-aged and elderly Iranian population. Nutritional interventions and population-based education to improve healthy diets among the studied population at risk are needed.

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