The Glymphatic System: A Beginner’s Guide
TL;DR: The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system.
Abstract: The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system also facilitates brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors, and neuromodulators. Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. Since the concept of the glymphatic system is relatively new, we will here review its basic structural elements, organization, regulation, and functions. We will also discuss recent studies indicating that glymphatic function is suppressed in various diseases and that failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.
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TL;DR: This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy.
Abstract: The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented
1,507 citations
TL;DR: The clearance systems of the brain as they relate to proteins implicated in AD pathology are described, with the main focus on Aβ.
Abstract: Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.
1,047 citations
TL;DR: This review examines molecular and cellular mechanisms underlying the establishment of the blood-brain barrier, and examines how BBB dysfunction relates to neurological deficits and other pathologies in the majority of sporadic AD, PD, and ALS cases, multiple sclerosis, other neurodegenerative disorders, and acute CNS disorders.
Abstract: The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of t...
1,033 citations
TL;DR: The interrelationships between Neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD are discussed, focusing on microglia as major players in neuro inflammation and how these cells could be modulated as a therapeutic strategy for AD.
Abstract: Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60–70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD. Accumulating evidence indicates important roles for microglial activation and neuroinflammation in Alzheimer disease (AD). Here, Leng and Edison describe the interplay between microglial activation and AD-related pathologies and discuss how microglial priming and activation might influence the trajectory of AD.
859 citations
TL;DR: If the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned, and lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.
Abstract: The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer's disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis "has all but supplanted the amyloid cascade." Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.
518 citations
Cites background from "The Glymphatic System: A Beginner’s..."
...The recently discovered glymphatic system functions to remove metabolic waste, including soluble proteins, from the CNS [360]....
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...Keywords: Alzheimer’s disease, amyloid- peptide, diagnostics, etiology, model systems, oligomers, prions, receptors, structure-function, tau, therapeutics Abbreviations: 7nAChR, alpha 7-nicotinic acetylcholine receptor; 5XFAD, transgenic mouse model of AD carrying 5 ADrelated familial mutations; A11, amyloid oligomer polyclonal antibody; A , Amyloid peptide; A 40, Amyloid peptide 1–40 sequence; A 42, Amyloid peptide 1–42 sequence; A 43, Amyloid peptide 1–43 sequence; A Os, A oligomers; AD, Alzheimer’s disease; AkT, Protein Kinase B; ALS, Amyotrophic lateral sclerosis; AMPA, -amino-3-hydroxy-5methylisoxazole-4-propionic acid receptor; APOE, Apolipoprotein E gene; ApoE, Apolipoprotein E; APP, Amyloid precursor protein; AFM, atomic force microscopy; BACE, -secretase; Ca++, calcium ion; CaMKII, Ca++/calmodulin-dependent protein kinase II; cDNA, complementary DNA; CNS, central nervous system; CSF, cerebrospinal fluid; CT, cortex; CTAD, Clinical Trials on Alzheimer’s Disease; CTE, chronic traumatic encephalopathy; DHA, docosahexaenoic acid; DPP4, dipeptidyl peptidase 4; EphB2, Ephrin type B receptor 2; EphA4, Ephrin type A receptor 4; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; Fab, fragment antigen-binding; fAD, Familial Alzheimer’s disease; FAK, focal adhesion kinase; Fc RIIb, Immunoglobulin gamma Fc region receptor II-b; FPR2, N-formyl peptide receptor 2; Fyn, tyrosine-protein kinase Fyn; GSK3 , glycogen synthase kinase 3 ; GTPase Drp-1, GTPase dynamin-related protein 1; HDAC6, histone deacetylase 6; HMW, high molecular weight; HP, hippocampus; i.c.v., intracerebroventricular; IGF-1, insulin-like growth factor 1; iPSC, induced pluripotent stem cells; IR, insulin receptor; IRS-1, insulin receptor substrate 1; kDa, kilodalton; ∗Correspondence to: Dr. William Klein, Department of Neurobiology, Northwestern University, Evanston, IL 60208, USA....
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...Glymphatic system and impaired AβO clearance The recently discovered glymphatic system func- tions to remove metabolic waste, including soluble proteins, from the CNS [360]....
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References
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TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Abstract: The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
8,669 citations
TL;DR: It is demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease.
Abstract: Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.
4,179 citations
"The Glymphatic System: A Beginner’s..." refers background in this paper
...maintaining homeostasis necessary for a healthy environment of the brain [60, 61]....
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TL;DR: An anatomically distinct clearing system in the brain that serves a lymphatic-like function is described and may have relevance for understanding or treating neurodegenerative diseases that involve the mis-accumulation of soluble proteins, such as amyloid β in Alzheimer's disease.
Abstract: Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
3,368 citations
TL;DR: It is reported that sleep has a critical function in ensuring metabolic homeostasis and convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep, suggesting the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
Abstract: The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
3,303 citations
"The Glymphatic System: A Beginner’s..." refers background or result in this paper
...Local application of a cocktail of norepinephrine receptor antagonists in awake mice resulted in an increase in CSF tracer influx almost comparable to that observed during sleep or anesthesia [80]....
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...that the CSF influx in the awake state was reduced by 90% compared to anesthetized mice [80]....
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...The sleep-wake difference in glymphatic influx correlated with the volume fraction of interstitial space that was 13-15% in the awake state an expanded to 22-24% in both sleep and anesthetized mice [80]....
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TL;DR: There is increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity, leading to approaches toward rational therapeutics.
Abstract: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.
2,926 citations
"The Glymphatic System: A Beginner’s..." refers background in this paper
...Indeed, all prevalent neurodegenerative diseases are characterized by accumulation of aggregated proteins [91]....
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