The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical and experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, and enhanced inflammation. These changes are associated with cognitive decline and neurobehavioral deficits. Although aging is not a disease, it is a significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, and general disease susceptibility. Conversely, life events related to mental stress and trauma can also lead to accelerated age-associated disorders and dementia. Here, we review human studies and studies on mice and rats, such as those modeling human neurodegenerative diseases, that have helped elucidate (1) the dynamics and mechanisms underlying the biological and pathological aging of the main projecting systems in the brain (glutamatergic, cholinergic, and dopaminergic) and (2) the effect of defective glutamatergic, cholinergic, and dopaminergic projection on disabilities associated with aging and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Detailed knowledge of the mechanisms of age-related diseases can be an important element in the development of effective ways of treatment. In this context, we briefly analyze which adverse changes associated with neurodegenerative diseases in the cholinergic, glutaminergic and dopaminergic systems could be targeted by therapeutic strategies developed as a result of our better understanding of these damaging mechanisms.

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Inflammaging and Brain: Curcumin and Its Beneficial Potential as Regulator of Microglia Activation

Molecules ◽

10.3390/molecules27020341 ◽

2022 ◽

Vol 27 (2) ◽

pp. 341

Author(s):

Antonia Cianciulli ◽

Rosa Calvello ◽

Melania Ruggiero ◽

Maria Antonietta Panaro

Keyword(s):

Neurodegenerative Diseases ◽

Curcuma Longa ◽

Significant Risk ◽

Significant Risk Factor ◽

Low Grade ◽

Beneficial Effects ◽

Positive Effects ◽

Age Related ◽

Brain Ageing ◽

The Brain

Inflammaging is a term used to describe the tight relationship between low-grade chronic inflammation and aging that occurs during physiological aging in the absence of evident infection. This condition has been linked to a broad spectrum of age-related disorders in various organs including the brain. Inflammaging represents a highly significant risk factor for the development and progression of age-related conditions, including neurodegenerative diseases which are characterized by the progressive dysfunction and degeneration of neurons in the brain and peripheral nervous system. Curcumin is a widely studied polyphenol isolated from Curcuma longa with a variety of pharmacologic properties. It is well-known for its healing properties and has been extensively used in Asian medicine to treat a variety of illness conditions. The number of studies that suggest beneficial effects of curcumin on brain pathologies and age-related diseases is increasing. Curcumin is able to inhibit the formation of reactive-oxygen species and other pro-inflammatory mediators that are believed to play a pivotal role in many age-related diseases. Curcumin has been recently proposed as a potential useful remedy against neurodegenerative disorders and brain ageing. In light of this, our current review aims to discuss the potential positive effects of Curcumin on the possibility to control inflammaging emphasizing the possible modulation of inflammaging processes in neurodegenerative diseases.

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453 - The effect of ageing in personality and emotions

International Psychogeriatrics ◽

10.1017/s1041610220003051 ◽

2020 ◽

Vol 32 (S1) ◽

pp. 173-173

Author(s):

Catarina Pedro ◽

Mariana Duarte ◽

Beatriz Jorge ◽

Daniela Freitas

Keyword(s):

Old Age ◽

Emotional Processing ◽

Personality Development ◽

Early Adulthood ◽

Significant Risk ◽

Marked Change ◽

Significant Risk Factor ◽

The Elderly ◽

Big Five Personality ◽

Age Related

Introduction:Personality and emotions have not been studied as thoroughly as cognition in old age. Recent research suggests personality changes across the entire life span, through middle age and even into old age. Thus, the previous assumption of stability in personality traits from early adulthood has been challenged and novel approaches to the study of personality development have emerged.Objectives:The aim of this presentation is to describe the effects of the ageing process in personality and emotions.Methods:A non-systematic review of the literature was performed on PubMed, PsycINFO and Web of science using selected keywords.Results:When older adults compare their current and past selves, they usually perceive a subjective growth in personality. Descriptive research suggests that the big five personality characteristics (neuroticism, extraversion, openness, agreeableness and conscientiousness) remain generally stable over the lifespan, despite variations in life experiences. Some studies revealed age-related linear decrease in extraversion. One of the studies found that hearing impairment, already identified as a significant risk factor for social isolation, was related to this decline in extraversion. Although levels of neuroticism tends to go down over the course of adulthood, the increased vulnerabilities that accompany old age may amplify neurotic traits, increasing worries about physical health and memory, common features of depression in the elderly. Emotions, relative to more neutral knowledge and skills, increase in later years. Elderly have better control over emotions than do younger adults, they reason more flexibly about emotion-laden dilemmas and remember emotionally charged information better than neutral facts. Older people also rely more often on emotion-focused forms of coping, as opposed to active, problem-solving approaches.Conclusions:Core features of personality seem to remain relatively stable throughout adulthood and any marked change in mood or social behavior may indicate a disorder. However, more subtle reordering of personal priorities and shifts in coping styles are common with normal ageing. The richness of emotional processing in older persons runs counter to the generally declining patterns seen in many cognitive and physical skills.

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Modulation of Bacterial Pathogenesis by Oppressive Aging Factors: Insights into Host-Pneumococcal Interaction Strategies

ISRN Inflammation ◽

10.5402/2012/267101 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Pooja Shivshankar

Keyword(s):

Cellular Senescence ◽

Significant Risk ◽

Significant Risk Factor ◽

The Elderly ◽

Receptor Expression ◽

Chronic Obstructive ◽

Related Phenomenon ◽

Aged Mice ◽

Inflammatory Status ◽

Age Related

Streptococcus pneumonia, (Spn, the pneumococcus), is the leading cause of community-acquired pneumonia (CAP) and is responsible for 15–40% deaths in the elderly worldwide. A primed inflammatory status is a significant risk factor for the increased severity of infectious diseases among the elderly (≥65 years of age). Studies have shown that expression of host receptors that the pneumococci bind to invade the tissues are increased thereby increasing the susceptibility to pneumococcal challenge in aged mice. Cellular senescence, an age-related phenomenon that leads to cell cycle arrest may also contribute to increased inflammation in aged mice. Evidence of cellular senescence in aged lungs of humans and mice adds credits to the concept of inflammaging and enhanced bacterial ligands expression during aging. Furthermore, cell senescence has been shown to occur in age-associated lung pathologies such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) that may predispose the elderly to pathogenic assaults, including S. pneumoniae. This review highlights the aspects of: chronic inflammation in the aged population; contribution of cellular senescence to age-associated inflammation and their impact on host receptor expression; and, increased susceptibility of fibrosis and emphysematous lesions-bearing lungs to microbial infections.

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Hip Fracture

Acute Pain Medicine ◽

10.1093/med/9780190856649.003.0020 ◽

2019 ◽

pp. 281-293

Author(s):

Franchesca Arias ◽

Catherine C. Price ◽

Jeffrey C. Gadsden

Keyword(s):

Risk Factor ◽

Hip Fracture ◽

Significant Risk ◽

Public Health Problem ◽

Significant Risk Factor ◽

The Elderly ◽

Age Related ◽

Significant Public Health ◽

Continuous Nerve Block ◽

Fascia Iliaca Block

This chapter discusses hip fracture, which is a significant public health problem associated with substantial morbidity and mortality. Pain with hip fracture is often severe but despite this is frequently undertreated in the elderly population. Untreated pain not only is inhumane but also is a significant risk factor for delirium in this population that is already at increased risk due to age-related cognitive decline. Hip fracture patients benefit from early intervention with regional analgesic techniques such as femoral or fascia iliaca block, as well as a scheduled regimen of nonopioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory medications. While opioids are known to contribute to risk for delirium, pain itself is a much stronger risk factor, and when nonopioid options are exhausted, opioids should be carefully considered. Continuous nerve block techniques provide opportunities for extended pain relief, which is associated with improved recovery profile, greater satisfaction, and a decreased risk for complications.

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Aging of Brain Related with Mitochondrial Dysfunctions

Current Drug Targets ◽

10.2174/1389450121999201209202247 ◽

2020 ◽

Vol 21 ◽

Author(s):

Vipin Dhote ◽

Prem Samundre ◽

Aditya Ganeshpurkar ◽

Aman Upaganlawar

Keyword(s):

Neurodegenerative Diseases ◽

Psychiatric Symptoms ◽

Neuronal Damage ◽

The Elderly ◽

Environmental Chemicals ◽

Aging Brain ◽

Mitochondrial Dysfunctions ◽

Mitochondrial Functions ◽

Key Issues ◽

The Brain

Abstract:: Advancing age presents a major challenge for the elderly population in terms of quality of life. The risk of cognitive impairment, motor in-coordination, and behavioral inconsistency due to neuronal damage is relatively higher in aging individuals of society. The brain, through its structural and functional integrity, regulates vital physiological events; however, the susceptibility of the brain to aging-related disturbances signal the onset of neurodegenerative diseases. Mitochondrial dysfunctions impair bioenergetic mechanism, synaptic plasticity, and calcium homeostasis in the brain, thus sufficiently implying mitochondria as a prime causal factor in accelerating aging-related neurodegeneration. We reviewed the fundamental functions of mitochondria in a healthy brain and aimed to address the key issues in aging-related diseases by asking: 1) What goes wrong with mitochondria in the aging brain? 2) What are the implications of mitochondrial damage on motor functions and psychiatric symptoms? 3) How environmental chemicals and metabolic morbidities affect mitochondrial functions? Further, we share insight on opportunities and pitfalls in drug discovery approaches targeting mitochondria to slow down the progression of aging and related neurodegenerative diseases.

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Novel Approaches for the Treatment of Alzheimer’s and Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20030719 ◽

2019 ◽

Vol 20 (3) ◽

pp. 719 ◽

Cited By ~ 38

Author(s):

Michiel Van Bulck ◽

Ana Sierra-Magro ◽

Jesus Alarcon-Gil ◽

Ana Perez-Castillo ◽

Jose Morales-Garcia

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Current Knowledge ◽

Chronic Illnesses ◽

Aging Brain ◽

Therapeutic Approaches ◽

Neurodegenerative Process ◽

Age Related ◽

Parkinson’S Diseases ◽

Current Therapies

Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer’s and Parkinson’s diseases. A progressive neurodegenerative process and neuroinflammation occur, and no current therapies can prevent, slow, or halt disease progression. To date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. Therefore, early diagnosis and the discovery of new targets and novel therapies are of upmost importance. Neurodegenerative diseases, like in other age-related disorders, the progression of pathology begins many years before the onset of symptoms. Many efforts in this field have led to the conclusion that exits some similar events among these diseases that can explain why the aging brain is so vulnerable to suffer neurodegenerative diseases. This article reviews the current knowledge about these diseases by summarizing the most common features of major neurodegenerative disorders, their causes and consequences, and the proposed novel therapeutic approaches.

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Energy Metabolism Decline in the Aging Brain; Pathogenesis of Neurodegenerative Disorders

10.20944/preprints202009.0539.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Janusz Błaszczyk

Keyword(s):

Energy Metabolism ◽

Neurodegenerative Diseases ◽

Krebs Cycle ◽

Brain Structures ◽

The Elderly ◽

Review Article ◽

Aging Brain ◽

Salvage Pathway ◽

Atp Production ◽

The Brain

A growing body of evidence indicates that aging of the brain is strictly related to the decline of energy metabolism. In particular, in older adults, the neuronal metabolism of glucose declines steadily resulting in a growing deficit of ATP production. The decline is evoked by deficient NAD recovery in the salvage pathway and subsequent impairment of the Krebs cycle. NAD deficit impairs also the activity of NAD-dependent enzymes. All these open vicious circles of neurodegeneration and neuronal death. Some brain structures are particularly prone to aging and neurodegeneration. These are pathological foci of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This review article summarizes the impacts and mutual relationships between metabolic processes both on neuronal and brain levels. It also provides directions on how to reduce the risk of neurodegeneration and protect the elderly against neurodegenerative diseases.

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Ocular Neurodegenerative Diseases: Interconnection between Retina and Cortical Areas

Cells ◽

10.3390/cells10092394 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2394

Author(s):

Nicoletta Marchesi ◽

Foroogh Fahmideh ◽

Federica Boschi ◽

Alessia Pascale ◽

Annalisa Barbieri

Keyword(s):

Neurodegenerative Diseases ◽

Light Stimulus ◽

The Elderly ◽

Cell Types ◽

Age Related Macular Degeneration ◽

Age Related ◽

Ocular Disorders ◽

Progressive Neurodegeneration ◽

Underlying Mechanisms ◽

The Brain

The possible interconnection between the eye and central nervous system (CNS) has been a topic of discussion for several years just based on fact that the eye is properly considered an extension of the brain. Both organs consist of neurons and derived from a neural tube. The visual process involves photoreceptors that receive light stimulus from the external environment and send it to retinal ganglionic cells (RGC), one of the cell types of which the retina is composed. The retina, the internal visual membrane of the eye, processes the visual stimuli in electric stimuli to transfer it to the brain, through the optic nerve. Retinal chronic progressive neurodegeneration, which may occur among the elderly, can lead to different disorders of the eye such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Mainly in the elderly population, but also among younger people, such ocular pathologies are the cause of irreversible blindness or impaired, reduced vision. Typical neurodegenerative diseases of the CSN are a group of pathologies with common characteristics and etiology not fully understood; some risk factors have been identified, but they are not enough to justify all the cases observed. Furthermore, several studies have shown that also ocular disorders present characteristics of neurodegenerative diseases and, on the other hand, CNS pathologies, i.e., Alzheimer disease (AD) and Parkinson disease (PD), which are causes of morbidity and mortality worldwide, show peculiar alterations at the ocular level. The knowledge of possible correlations could help to understand the mechanisms of onset. Moreover, the underlying mechanisms of these heterogeneous disorders are still debated. This review discusses the characteristics of the ocular illnesses, focusing on the relationship between the eye and the brain. A better comprehension could help in future new therapies, thus reducing or avoiding loss of vision and improve quality of life.

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The aging mind: neuroplasticity in response to cognitive training

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2013.15.1/dpark ◽

2013 ◽

Vol 15 (1) ◽

pp. 109-119 ◽

Cited By ~ 48

Keyword(s):

Cognitive Function ◽

Cognitive Training ◽

Neural Plasticity ◽

Cognitive Effort ◽

Aging Brain ◽

Cognitive Domains ◽

Training Techniques ◽

Age Related ◽

Strategy Change ◽

The Brain

Is it possible to enhance neural and cognitive function with cognitive training techniques? Can we delay age-related decline in cognitive function with interventions and stave off Alzheimer's disease? Does an aged brain really have the capacity to change in response to stimulation? In the present paper, we consider the neuroplasticity of the aging brain, that is, the brain's ability to increase capacity in response to sustained experience. We argue that, although there is some neural deterioration that occurs with age, the brain has the capacity to increase neural activity and develop neural scaffolding to regulate cognitive function. We suggest that increase in neural volume in response to cognitive training or experience is a clear indicator of change, but that changes in activation in response to cognitive training may be evidence of strategy change rather than indicative of neural plasticity. We note that the effect of cognitive training is surprisingly durable over time, but that the evidence that training effects transfer to other cognitive domains is relatively limited. We review evidence which suggests that engagement in an environment that requires sustained cognitive effort may facilitate cognitive function.

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Abstract TMP82: Increased Intracerebral Hemorrhage During Acute and Chronic Hypertension in Alzheimer's Transgenic Mice

Stroke ◽

10.1161/str.44.suppl_1.atmp82 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

David H Cribbs ◽

Giselle Passos ◽

Vitaly Vasilevko

Keyword(s):

Risk Factor ◽

Transgenic Mice ◽

Intracerebral Hemorrhage ◽

Amyloid Precursor Protein ◽

Significant Risk ◽

Significant Risk Factor ◽

Chronic Hypertension ◽

Cerebrovascular System ◽

The Brain ◽

Tg2576 Mice

Hypertension is a major risk factor for intracerebral hemorrhage (ICH), and the accumulation of amyloid-beta (Aβ) in the cerebrovascular system, cerebral amyloid angiopathy (CAA), is also a significant risk factor for intracerebral hemorrhage ICH. Currently, there are no animal studies demonstrating a direct involvement of hypertension in the accumulation of Alzheimer’s disease-like pathology. To address this issue we have developed several mouse models that combine hypertension protocols with amyloid precursor protein (APP) transgenic mice (Tg2576), which accumulate significant CAA in the large cerebral vessels and the meninges by 18 months of age. The goal of this study was to determine the effect of acute and chronic hypertension on ICH in wildtype and a transgenic mouse model overexpressing a mutant human amyloid precursor protein (Tg2576 mice) associated with early onset AD and CAA. Fifteen-month-old Tg2576 mice and non-transgenic (nTg) littermates were treated with an angiotensin II (AngII) infusion (1000 ng/kg/min) and L-NAME (100 mg/kg/day) in drinking water to produce chronic hypertension. One week later, transient acute hypertension was induced by daily AngII injections (0.5 μg/g, s.c., twice daily) to produce ICH. A similar increase in mean blood pressure was observed in Tg2576 and nTg mice when evaluated 2 weeks after initiation of treatment. However Tg2576 mice had a higher incidence of signs of stroke compared with nTg littermates (P > 0.05). These data suggest that the accumulation of Aβ in the brain has an important role in development of ICH. Moreover, there was robust glial activation and increase in CAA in the gray matter of Tg2576 mice showing that hypertension may affect gray as well as white matter in the brain. Further studies may provide insights into the hypertension-induced changes in the cerebral vascular system that initiated the increase in CAA. The accumulation of Aβ in the cerebrovascular system is a significant risk factor for intracerebral hemorrhage (ICH), and has been linked to endothelial transport failure and blockage of perivascular drainage. While management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA.

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