Achieving brain clearance and preventing neurodegenerative diseases—A glymphatic perspective

Age-related neurodegenerative diseases are a growing burden to society, and many are sporadic, meaning that the environment, diet and lifestyle play significant roles. Cerebrospinal fluid (CSF)-mediated clearing of brain waste products via perivascular pathways, named the glymphatic system, is receiving increasing interest, as it offers unexplored perspectives on understanding neurodegenerative diseases. The glymphatic system is involved in clearance of metabolic by-products such as amyloid-β from the brain, and its function is believed to lower the risk of developing some of the most common neurodegenerative diseases. Here, we present magnetic resonance imaging (MRI) data on the heart cycle’s control of CSF flow in humans which corroborates findings from animal studies. We also review the importance of sleep, diet, vascular health for glymphatic clearance and find that these factors are also known players in brain longevity.

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Brain lymphatic drainage system – visualization opportunities and current state of the art

Complex Issues of Cardiovascular Diseases ◽

10.17802/2306-1278-2020-9-3-81-89 ◽

2020 ◽

Vol 9 (3) ◽

pp. 81-89

Author(s):

G. S. Yankova ◽

O. B. Bogomyakova

Keyword(s):

Neurodegenerative Diseases ◽

Immune Surveillance ◽

Lymphatic Vessels ◽

Drainage System ◽

Lymphatic Drainage ◽

Waste Products ◽

Glymphatic System ◽

Age Related ◽

The Central Nervous System ◽

The Brain

The lymphatic drainage system of the brain is assumed to consist of the lymphatic system and a network of meningeal lymphatic vessels. This system supports brain homeostasis, participates in immune surveillance and presents a new therapeutic target in the treatment of neurological disorders.The article analyzes and systematizes data on the brain lymphatic drainage system. The key components of this system are considered: recently described meningeal lymphatic vessels and their relationship with the glymphatic system, which provides perfusion of the central nervous system with cerebrospinal and interstitial fluids. The lymphatic drainage system helps to maintain water and ion balances of the interstitial fluid and to remove metabolic waste products, assists in reabsorption of macromolecules. Disorders in its work play a crucial role in age-related changes in the brain, the pathogenesis of neurovascular and neurodegenerative diseases, as well as injuries and brain tumors. The review also presents the results of human studies concerning the presence, anatomy and structure of meningeal lymphatic vessels and the glymphatic system. The discovery of the brain lymphatic drainage system has not only changed our understanding of cerebrospinal fluid circulation, but also contributed to understanding the pathology and mechanisms of neurodegenerative diseases.

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The glymphatic system and meningeal lymphatics of the brain: new understanding of brain clearance

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0106 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Galina Yankova ◽

Olga Bogomyakova ◽

Andrey Tulupov

Keyword(s):

Neurodegenerative Diseases ◽

Brain Injuries ◽

Immune Surveillance ◽

Lymphatic Vessels ◽

Drainage System ◽

Waste Products ◽

Glymphatic System ◽

System A ◽

Age Related ◽

The Brain

Abstract The glymphatic system and meningeal lymphatics have recently been characterized. Glymphatic system is a glia-dependent system of perivascular channels, and it plays an important role in the removal of interstitial metabolic waste products. The meningeal lymphatics may be a key drainage route for cerebrospinal fluid into the peripheral blood, may contribute to inflammatory reaction and central nervous system (CNS) immune surveillance. Breakdowns and dysfunction of the glymphatic system and meningeal lymphatics play a crucial role in age-related brain changes, the pathogenesis of neurovascular and neurodegenerative diseases, as well as in brain injuries and tumors. This review discusses the relationship recently characterized meningeal lymphatic vessels with the glymphatic system, which provides perfusion of the CNS with cerebrospinal and interstitial fluids. The review also presents the results of human studies concerning both the presence of meningeal lymphatics and the glymphatic system. A new understanding of how aging, medications, sleep and wake cycles, genetic predisposition, and even body posture affect the brain drainage system has not only changed the idea of brain fluid circulation but has also contributed to an understanding of the pathology and mechanisms of neurodegenerative diseases.

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Neural glymphatic system: Clinical implications and potential importance of melatonin

Melatonin Research ◽

10.32794/mr112500111 ◽

2021 ◽

Vol 4 (4) ◽

pp. 551-565

Author(s):

Ryan D Bitar ◽

Jorge L Torres-Garza ◽

Russel J Reiter ◽

William T Phillips

Keyword(s):

Lymph Nodes ◽

Subarachnoid Space ◽

Slow Wave Sleep ◽

Lymphatic Vessels ◽

Amyloid Β ◽

Secretory Product ◽

Cervical Lymph Nodes ◽

Waste Products ◽

Glymphatic System ◽

The Brain

The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system. This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively. The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces. Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin. Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia. Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.

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The Sleeping Brain: Harnessing the Power of the Glymphatic System through Lifestyle Choices

Brain Sciences ◽

10.3390/brainsci10110868 ◽

2020 ◽

Vol 10 (11) ◽

pp. 868

Author(s):

Oliver Cameron Reddy ◽

Ysbrand D. van der Werf

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Risk ◽

Intermittent Fasting ◽

Waste Products ◽

Glymphatic System ◽

Age Related ◽

Lifestyle Choices ◽

Brain Ageing ◽

The Brain

The glymphatic system is a “pseudo-lymphatic” perivascular network distributed throughout the brain, responsible for replenishing as well as cleansing the brain. Glymphatic clearance is the macroscopic process of convective fluid transport in which harmful interstitial metabolic waste products are removed from the brain intima. This paper addresses the glymphatic system, its dysfunction and the major consequences of impaired clearance in order to link neurodegeneration and glymphatic activity with lifestyle choices. Glymphatic clearance can be manipulated by sleep deprivation, cisterna magna puncture, acetazolamide or genetic deletion of AQP4 channels, but how lifestyle choices affect this brain-wide clearance system remains to be resolved. This paper will synthesize existing literature on glymphatic clearance, sleep, Alzheimer’s disease and lifestyle choices, in order to harness the power of this mass transport system, promote healthy brain ageing and possibly prevent neurodegenerative processes. This paper concludes that 1. glymphatic clearance plays a major role in Alzheimer’s pathology; 2. the vast majority of waste clearance occurs during sleep; 3. dementias are associated with sleep disruption, alongside an age-related decline in AQP4 polarization; and 4. lifestyle choices such as sleep position, alcohol intake, exercise, omega-3 consumption, intermittent fasting and chronic stress all modulate glymphatic clearance. Lifestyle choices could therefore alter Alzheimer’s disease risk through improved glymphatic clearance, and could be used as a preventative lifestyle intervention for both healthy brain ageing and Alzheimer’s disease.

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Glymphatic failure as a final common pathway to dementia

Science ◽

10.1126/science.abb8739 ◽

2020 ◽

Vol 370 (6512) ◽

pp. 50-56 ◽

Cited By ~ 3

Author(s):

Maiken Nedergaard ◽

Steven A. Goldman

Keyword(s):

Neurodegenerative Diseases ◽

Common Pathway ◽

Waste Products ◽

Glymphatic System ◽

Final Common Pathway ◽

Protein Waste ◽

Evolutionarily Conserved ◽

Impaired Sleep ◽

Neurodegenerative Dementias ◽

The Brain

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.

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Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

Journal of Alzheimer s Disease ◽

10.3233/jad-215128 ◽

2021 ◽

pp. 1-14

Author(s):

Andrew L. Zhou ◽

Nidhi Sharda ◽

Vidur V. Sarma ◽

Kristen M. Ahlschwede ◽

Geoffry L. Curran ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Single Photon ◽

Photon Emission ◽

Amyloid Β ◽

Emission Computed Tomography ◽

Systemic Injection ◽

Age Related ◽

Age Dependent ◽

Plasma Pharmacokinetics ◽

The Brain

Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ 40, 125I-Aβ 42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ 40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ 40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

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Role of the glymphatic system in ageing and diabetes mellitus impaired cognitive function

Stroke and Vascular Neurology ◽

10.1136/svn-2018-000203 ◽

2019 ◽

Vol 4 (2) ◽

pp. 90-92 ◽

Cited By ~ 6

Author(s):

Li Zhang ◽

Michael Chopp ◽

Quan Jiang ◽

Zhenggang Zhang

Keyword(s):

Diabetes Mellitus ◽

Cognitive Impairment ◽

Interstitial Fluid ◽

Amyloid Β ◽

Brain Parenchyma ◽

Glymphatic System ◽

Impaired Cognitive Function ◽

Increased Risk ◽

The Brain

Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment.

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Effect of Sleep Deprivation on the Hippocampus of Adult and Senile Male Albino Rat: A Histological and Histochemical Study

QJM ◽

10.1093/qjmed/hcaa040.003 ◽

2020 ◽

Vol 113 (Supplement_1) ◽

Author(s):

S S I Elkilany ◽

M M A Zakaria ◽

R F Tash ◽

A Y Mostafa ◽

S W Abdelmalik ◽

...

Keyword(s):

Sleep Deprivation ◽

Dentate Gyrus ◽

Therapeutic Strategy ◽

Control Group ◽

Albino Rats ◽

Free Access ◽

Waste Products ◽

Glymphatic System ◽

The Impact ◽

The Brain

Abstract Background The importance of sleep and the impact of its deprivation on development of brain pathology became a recent subject of interest in medicine. The restorative effect of sleep on the brain and the harmful effects of insomnia have been recently revealed through the discovery of the glymphatic system and its association with sleep. Aim of work Specific objectives are: To detect histological and apoptotic changes in the neurons and dendrites of the cornu Amonis and the dentate gyrus in sleep deprived rats in comparison to rats with undisturbed sleep pattern (control). To detect deposition of neurotoxic metabolites in comu Amonis and dentate gyrus in sleep deprived rats in comparison to controls. Methods Twenty four adult male Albino rats were used in the present experiment. randomly categorized into four equal groups; Group A1 served as the control group, Group .A2 one day sleep deprivation, Group A3 three days sleep deprivation and Group A4 seven days sleep deprivation. They were deprived of sleep using grid over water method where the animals placed over a grid suspended above tank filled with water with free access to food (rat chew) and water. Hippocampai specimens were collected, processed for paraffin blocks and examined by light microscopy. Results there were neurodegenerative signs appeared from day one sleep deprivation, increased by day three and prevailed by day seven. It was confirmed by apoptotic changes detected by caspase 3 immunohistochemical staining. Furthermore, deposition of beta amyloid appeared in rats deprived of sleep and confirmed by congo red stain. Conclusion Adequate sleep is essential for integrity of the newly discovered glymphatic system responsible for clearance of the brain from waste products including the area most involved in learning and memory function; the hippocampus. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD. Recommendations Further characterization of the glymphatic system in humans are required, it may lead to new therapies and methods of prevention of neurodegenerative diseases. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD.

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Omega‐3 polyunsaturated fatty acids promote amyloid‐β clearance from the brain through mediating the function of the glymphatic system

The FASEB Journal ◽

10.1096/fj.201600896 ◽

2016 ◽

Vol 31 (1) ◽

pp. 282-293 ◽

Cited By ~ 38

Author(s):

Huixia Ren ◽

Chuanming Luo ◽

Yanqing Feng ◽

Xiaoli Yao ◽

Zhe Shi ◽

...

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Amyloid Β ◽

Omega 3 ◽

Glymphatic System ◽

The Brain

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6-gingerol interferes with amyloid-beta (Aβ) peptide aggregation

10.1101/2021.01.03.425159 ◽

2021 ◽

Author(s):

Elina Berntsson ◽

Suman Paul ◽

Sabrina B. Sholts ◽

Jüri Jarvet ◽

Andreas Barth ◽

...

Keyword(s):

Animal Studies ◽

Amyloid Fibrils ◽

Amyloid Β ◽

Nutritional Supplement ◽

Aβ Oligomers ◽

Microscopy Imaging ◽

Positive Effects ◽

Age Related ◽

Soluble Aβ Oligomers

AbstractAlzheimer’s disease (AD) is the most prevalent age-related cause of dementia. AD affects millions of people worldwide, and to date there is no cure. The pathological hallmark of AD brains is deposition of amyloid plaques, which mainly consist of amyloid-β (Aβ) peptides, commonly 40 or 42 residues long, that have aggregated into amyloid fibrils. Intermediate aggregates in the form of soluble Aβ oligomers appear to be highly neurotoxic. Cell and animal studies have previously demonstrated positive effects of the molecule 6-gingerol on AD pathology. Gingerols are the main active constituents of the ginger root, which in many cultures is a traditional nutritional supplement for memory enhancement. Here, we use biophysical experiments to characterize in vitro interactions between 6-gingerol and Aβ40 peptides. Our experiments with atomic force microscopy imaging, and nuclear magnetic resonance and Thioflavin-T fluorescence spectroscopy, show that the hydrophobic 6-gingerol molecule interferes with formation of Aβ40 aggregates, but does not interact with Aβ40 monomers. Thus, together with its favourable toxicity profile, 6-gingerol appears to display many of the desired properties of an anti-AD compound.

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