scholarly journals Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage

2020 ◽  
Author(s):  
Thomas D. Prevot ◽  
Akiko Sumitomo ◽  
Toshifumi Tomoda ◽  
Daniel E. Knutson ◽  
Guanguan Li ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Cognitive Decline ◽  
Neuronal Morphology ◽  
Aging Brain ◽  
Primary Neuronal Culture ◽  
Efficient Treatment ◽  
Gaba A ◽  
Age Related ◽  
Β Amyloid ◽  
The Brain

ABSTRACTOver the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years. With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death. Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer’s disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.

scholarly journals Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

2021 ◽  
Vol 7 (21) ◽  
pp. eabe4601
Author(s):  
Sandro Da Mesquita ◽  
Jasmin Herz ◽  
Morgan Wall ◽  
Taitea Dykstra ◽  
Kalil Alves de Lima ◽  
...  
Keyword(s):  
T Cells ◽  
Cognitive Decline ◽  
Brain Aging ◽  
Therapeutic Potential ◽  
T Cell Response ◽  
Age Related ◽  
Lymphatic Vasculature ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

scholarly journals The aging mind: neuroplasticity in response to cognitive training

2013 ◽  
Vol 15 (1) ◽  
pp. 109-119 ◽  
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.

Aging

2019 ◽  
pp. 105-112
Author(s):  
Risto Näätänen ◽  
Teija Kujala ◽  
Gregory Light
Keyword(s):  
Hearing Loss ◽  
Speech Perception ◽  
Cognitive Decline ◽  
Temporal Processing ◽  
Brain Aging ◽  
Brain Plasticity ◽  
Part Of Speech ◽  
Memory Traces ◽  
Age Related ◽  
The Brain

This chapter shows that MMN and its magnetoencephalographic (MEG) equivalent MMNm are sensitive indices of aging-related perceptual and cognitive decline. Importantly, the age-related neural changes are associated with a decrease of general brain plasticity, i.e. that of the ability of the brain to form and maintain sensory-memory traces, a necessary basis for veridical perception and appropriate cognitive brain function. MMN/MMNm to change in stimulus duration is particularly affected by aging, suggesting the increased vulnerability of temporal processing to brain aging and accounting, for instance, for a large part of speech-perception difficulties of the aged beyond the age-related peripheral hearing loss.

scholarly journals Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

2021 ◽  
Vol 22 (19) ◽  
pp. 10251
Author(s):  
Vladimir Sukhorukov ◽  
Dmitry Voronkov ◽  
Tatiana Baranich ◽  
Natalia Mudzhiri ◽  
Alina Magnaeva ◽  
...  
Keyword(s):  
Glial Cells ◽  
Brain Aging ◽  
Cellular Level ◽  
Aging Brain ◽  
The Past ◽  
Age Related ◽  
Accumulation Of Damage ◽  
Quantity Control ◽  
The Brain

Aging is associated with a decline in cognitive function, which can partly be explained by the accumulation of damage to the brain cells over time. Neurons and glia undergo morphological and ultrastructure changes during aging. Over the past several years, it has become evident that at the cellular level, various hallmarks of an aging brain are closely related to mitophagy. The importance of mitochondria quality and quantity control through mitophagy is highlighted by the contribution that defects in mitochondria–autophagy crosstalk make to aging and age-related diseases. In this review, we analyze some of the more recent findings regarding the study of brain aging and neurodegeneration in the context of mitophagy. We discuss the data on the dynamics of selective autophagy in neurons and glial cells during aging and in the course of neurodegeneration, focusing on three mechanisms of mitophagy: non-receptor-mediated mitophagy, receptor-mediated mitophagy, and transcellular mitophagy. We review the role of mitophagy in neuronal/glial homeostasis and in the molecular pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and other disorders. Common mechanisms of aging and neurodegeneration that are related to different mitophagy pathways provide a number of promising targets for potential therapeutic agents.

scholarly journals Association between plasma phospho-tau181 and cognitive change from age 73 to 82: Lothian Birth Cohort 1936

2021 ◽  
Author(s):  
Tyler S Saunders ◽  
Amanda Heslegrave ◽  
Declan King ◽  
Sarah Harris ◽  
Craig W Ritchie ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Cognitive Change ◽  
Synaptic Function ◽  
Blood Biomarker ◽  
Array Tomography ◽  
Age Related ◽  
Lothian Birth Cohort ◽  
Synapse Degeneration ◽  
Age Related Cognitive Decline ◽  
The Brain

INTRODUCTION: Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer's disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we tested whether plasma p-tau181predicts cognitive decline and whether it is present in synapses in human brain. METHODS: General cognitive ability and plasma p-tau181 concentration were measured in 195 participants at ages 72 and 82. Levels of p-tau181 in total homogenate and synaptic fractions were compared with western blot (n=10-12 per group), and synaptic localisation was examined using array tomography. RESULTS: Elevated baseline plasma p-tau181 and increasing p-tau181 over time predicted steeper general cognitive decline. We observe p-tau181 in neurites, presynapses, and post-synapses in the brain. DISCUSSION: Baseline and subsequent change in plasma p-tau181 may represent rare biomarkers of differences in cognitive ageing across the 8th decade of life and may play a role in synaptic function in the brain.

scholarly journals Space-Dependent Glia–Neuron Interplay in the Hippocampus of Transgenic Models of β-Amyloid Deposition

2020 ◽  
Vol 21 (24) ◽  
pp. 9441
Author(s):  
Daniele Lana ◽  
Filippo Ugolini ◽  
Maria Grazia Giovannini
Keyword(s):  
Brain Regions ◽  
Therapeutic Strategies ◽  
Differential Sensitivity ◽  
Transgenic Models ◽  
Age Related ◽  
Neurodegenerative Pathology ◽  
Spatial Differences ◽  
Key Factor ◽  
Β Amyloid ◽  
The Brain

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer’s disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD’s histopathological hallmarks is the deposition of amyloid beta (Aβ) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies.

N-acetyl-l-cysteine attenuates oxidative damage and neurodegeneration in rat brain during aging

2018 ◽  
Vol 96 (12) ◽  
pp. 1189-1196 ◽  
Author(s):  
Geetika Garg ◽  
Sandeep Singh ◽  
Abhishek Kumar Singh ◽  
Syed Ibrahim Rizvi
Keyword(s):  
Rat Brain ◽  
Neuroprotective Effect ◽  
Neuron Specific Enolase ◽  
Sirtuin 1 ◽  
Marker Genes ◽  
Aging Brain ◽  
Age Related ◽  
Nonenzymatic Antioxidants ◽  
Old Rats ◽  
The Brain

N-acetyl-l-cysteine (NAC) is a precursor of cysteine, which is known to increase the level of glutathione (GSH) in the brain. Several neurodegenerative changes linked to oxidative stress take place in the aging brain. This study aimed to assess the neuroprotective effect of NAC supplementation on age-dependent neurodegeneration in the rat brain. Young (4 months) and old (24 months) Wistar rats (n = 6 rats/group) were supplemented with NAC (100 mg/kg b.w. orally) for 14 days. Enzymatic and nonenzymatic antioxidants such as superoxide dismutase and catalase, and GSH and total thiol respectively, prooxidants such as protein carbonyl, advanced oxidation protein products, reactive oxygen species, and malondialdehyde were assessed in the brain homogenates. Furthermore, nitric oxide level, acetylcholinesterase activity, and Na+/K+–ATPase activity were measured and gene expression studies were also performed. The results indicated that NAC augmented the level of enzymatic and nonenzymatic antioxidants with a significant reduction in prooxidant levels in old rats. NAC supplementation also downregulated the expression of inflammatory markers (TNF-α, IL-1β, IL-6) and upregulated the expression of marker genes associated with aging (sirtuin-1) and neurodegeneration (neuron-specific enolase, neuroglobin, synapsin-I, myelin basic protein 2) in old rats. The present findings support a neuroprotective role of NAC which has therapeutic implication in controlling age-related neurological disorders.

083 Response to immunosuppressive therapy in cerebral amyloid angiopathy-related inflammation

2018 ◽  
Vol 89 (6) ◽  
pp. A33.3-A34
Author(s):  
Jasmin Tilling ◽  
Benjamin Trewin ◽  
Stanley Levy
Keyword(s):  
White Matter ◽  
Cognitive Decline ◽  
Cerebral Amyloid Angiopathy ◽  
White Matter Hyperintensities ◽  
Neurological Deficits ◽  
Amyloid Angiopathy ◽  
Dramatic Improvement ◽  
Age Related ◽  
Cerebral Amyloid ◽  
The Brain

IntroductionCerebral amyloid angiopathy (CAA) is a common age-related condition characterised by amyloid beta-peptide deposition affecting the medium sized cortical and leptomeningeal arteries, arterioles and capillaries. CAA-related Inflammation (CAA-I) is an increasingly recognised variant of CAA, which is thought to be due to perivascular auto-inflammation in response to amyloid deposition. We describe the clinical course of two cases of probable CAA-I.CasesA 71 year old man presented with new-onset seizures, headaches and subacute cognitive decline. MRI of the brain demonstrated confluent subcortical T2 white matter hyperintensities and cerebral oedema, with predominantly superimposed widespread cortico-subcortical micro-haemorrhages, in keeping with the diagnosis of CAA-I. A course of immunosuppresive therapy was commenced with five days of intravenous methylprednisolone, resulting in marked radiological and clinical improvement within two weeks.A 76 year old female presented with subacute cognitive dysfunction and apraxia, and transient left-sided weakness. MRI scan of the brain initially demonstrated a right temporo-occipital infarct, leading to primary treatment for stroke, but subsequently evolved to reveal diffuse multi-lobar T2 white matter hyperintensities with leptomeningeal involvement. A provisional diagnosis of CAA-I was made and following a poor clinical response to a trial of corticosteroid therapy, treatment with intravenous cyclophosphamide was commenced.ConclusionThese cases emphasise the importance of CAA-I as part of the differential diagnosis in patients presenting with symptoms of subacute cognitive decline, seizures, headaches and focal neurological deficits, given the potential for dramatic improvement with readily accessible immunosuppressive therapies.

scholarly journals Aging Brain: Prevention of Oxidative Stress by Vitamin E and Exercise

2009 ◽  
Vol 9 ◽  
pp. 366-372 ◽  
Author(s):  
Sambe Asha Devi
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Cognitive Decline ◽  
Middle Age ◽  
Neuronal Loss ◽  
Aging Brain ◽  
Key Factors ◽  
Esterase Inhibitors ◽  
The Brain ◽  
And Oxidative Stress

With aging, the brain undergoes neuronal loss in many areas. Although the loss of cells in the cerebral cortex, in particular the frontal cortex, has been recognized with aging, the influence of synaptic losses has a larger impact on cognitive decline. Much of the recent research on animals, as well as humans, has been aimed at slowing the cognitive decline through enrichment, and it has been found that the key factors are antioxidants and exercise. Several reports support the concept that regular supplementation of vitamin E and physical activity from as early as middle age can slow the cognitive decline observed during the later years. A few studies have also suggested that exercise is analogous to acetylcholine esterase inhibitors that are also used extensively to treat cognitive impairment and dementia in Alzheimer's disease. In addition, reports also support that vitamin E and exercise may act synergistically to overcome free radical injury and oxidative stress in the aging brain.

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