Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2020, Номер 15(1)

Опубликована: Июль 16, 2020

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There currently no effective treatment for AD, which may be attributed part to lack of a clear underlying mechanism. Studies within last few decades provide growing evidence central role amyloid β (Aβ) and tau, as well glial contributions various molecular cellular pathways AD pathogenesis. Herein, we review recent progress with respect Aβ- tau-associated mechanisms, discuss dysfunction emphasis on neuronal receptors that mediate Aβ-induced toxicity. We also other critical factors affect pathogenesis, including genetics, aging, variables related environment, lifestyle habits, describe potential apolipoprotein E (APOE), viral bacterial infection, sleep, microbiota. Although have gained much towards understanding aspects this devastating disorder, greater commitment research mechanism, diagnostics will needed future research.

Язык: Английский

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Glymphatic failure as a final common pathway to dementia

Science, Год журнала: 2020, Номер 370(6512), С. 50 - 56

Опубликована: Окт. 2, 2020

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

Язык: Английский

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The blood–brain barrier in health and disease: Important unanswered questions

The Journal of Experimental Medicine, Год журнала: 2020, Номер 217(4)

Опубликована: Март 25, 2020

The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control movement ions, molecules, and cells between parenchyma. This “blood–brain barrier” is initiated during angiogenesis via signals from surrounding neural environment, its integrity remains vital for homeostasis protection throughout life. Blood–brain barrier dysfunction contributes to pathology in range neurological conditions including multiple sclerosis, stroke, epilepsy, has also been implicated neurodegenerative diseases such as Alzheimer’s disease. review will discuss current knowledge key unanswered questions regarding blood–brain health

Язык: Английский

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Sleep Spindles: Mechanisms and Functions

Physiological Reviews, Год журнала: 2019, Номер 100(2), С. 805 - 868

Опубликована: Дек. 5, 2019

Sleep spindles are burstlike signals in the electroencephalogram (EEG) of sleeping mammalian brain and electrical surface correlates neuronal oscillations thalamus. As one most inheritable sleep EEG signatures, probably reflect strength malleability thalamocortical circuits that underlie individual cognitive profiles. We review characteristics, organization, regulation, origins their implication non-rapid-eye-movement (NREMS) its functions, focusing on human rodent. Spatially, spindle-related activity appears scales ranging from small thalamic to functional cortical areas, generates a state favoring intracortical plasticity while limiting output. Temporally, discrete events, part continuous power band, elements grouped an infraslow time scale over which NREMS alternates between continuity fragility. synthesize diverse seemingly unlinked functions for architecture, sensory processing, synaptic plasticity, memory formation, abilities into unifying spindle concept, according 1) generate neural conditions large-scale connectivity outlast appearance as 2) appear preferentially engaged learning attention-based experience during wakefulness, 3) enable selective reactivation routing wake-instated traces areas such hippocampus cortex. Their fine spatiotemporal organization reflects physiological coordinated body may indicate, if not anticipate ultimately differentiate, pathologies neurodevelopmental, -degenerative, -psychiatric conditions.

Язык: Английский

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Revisiting the neurovascular unit

Nature Neuroscience, Год журнала: 2021, Номер 24(9), С. 1198 - 1209

Опубликована: Авг. 5, 2021

Язык: Английский

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The Brain’s Glymphatic System: Current Controversies

Trends in Neurosciences, Год журнала: 2020, Номер 43(7), С. 458 - 466

Опубликована: Май 15, 2020

The glymphatic concept along with the discovery of meningeal lymphatic vessels have, in recent years, highlighted that fluid is directionally transported within central nervous system (CNS). Imaging studies, as well manipulations transport, point to a key role glymphatic-lymphatic clearance amyloid-β and other proteins. As such, represents new target combating neurodegenerative diseases. Not unexpectedly, introduction plumbing brain has stirred controversies. This opinion article will highlight what we know about brain's transport systems, where experimental data are lacking, still debated.

Язык: Английский

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Circadian Mechanisms in Medicine

New England Journal of Medicine, Год журнала: 2021, Номер 384(6), С. 550 - 561

Опубликована: Фев. 10, 2021

Molecular insights into diurnal variations in human physiology and behavior are extending our understanding of a wide range disease processes. Chronobiology is also providing testable hypotheses regarding the timing treatments.

Язык: Английский

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Fluid transport in the brain

Physiological Reviews, Год журнала: 2021, Номер 102(2), С. 1025 - 1151

Опубликована: Май 5, 2021

The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. blood-brain barrier establishes stable environment that optimal for neuronal function, yet imposes physiological problem; transcapillary filtration forms extracellular fluid in other organs reduced to minimum brain. Consequently, depends on special [the cerebrospinal (CSF)] flushed into along perivascular spaces created by astrocytic vascular endfeet. We describe this pathway, coined term glymphatic system, based dependency endfeet their adluminal expression of aquaporin-4 water channels facing CSF-filled spaces. Glymphatic clearance potentially harmful metabolic or protein waste products, such as amyloid-β, primarily active sleep, when drivers, cardiac cycle, respiration, slow vasomotion, together efficiently propel CSF inflow periarterial brain's space contains an abundance proteoglycans hyaluronan, which provide low-resistance hydraulic conduit rapidly can expand shrink sleep-wake cycle. system brain, meets requisites maintain homeostasis similar peripheral organs, considering blood-brain-barrier paths formation egress CSF.

Язык: Английский

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Sleep deprivation impairs molecular clearance from the human brain

Brain, Год журнала: 2020, Номер 144(3), С. 863 - 874

Опубликована: Дек. 5, 2020

It remains an enigma why human beings spend one-third of their life asleep. Experimental data suggest that sleep is required for clearance waste products from brain metabolism. This has, however, never been verified in humans. The primary aim the present study was to examine vivo whether one night total deprivation affects molecular brain. Secondarily, we examined affected by subsequent sleep. Multiphase MRI with standardized T1 sequences performed up 48 h after intrathecal administration contrast agent gadobutrol (0.5 ml 1 mmol/ml), which served as a tracer molecule. Using FreeSurfer software, quantified enrichment within 85 regions percentage change baseline normalized signals. cerebral compared between two cohorts individuals; cohort (n = 7) underwent Day 2 (sleep group) while age and gender-matched control group 17; allowed free 2. From 3 all individuals were enriched brains groups similarly. Sleep sole intervention. One impaired substance most regions, including cortex, white matter limbic structures, demonstrated on morning intervention deprivation/sleep). Moreover, not compensated 3. results provide evidence impairs brain, humans do catch lost

Язык: Английский

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The Glymphatic System: A Novel Component of Fundamental Neurobiology

Journal of Neuroscience, Год журнала: 2021, Номер 41(37), С. 7698 - 7711

Опубликована: Сен. 15, 2021

Throughout the body, lymphatic fluid movement supports critical functions including clearance of excess and metabolic waste. The glymphatic system is analog in CNS. As such, plays a key role regulating directional interstitial movement, waste clearance, and, potentially, brain immunity. enables bulk CSF from subarachnoid space along periarterial spaces, where it mixes with within parenchyma before ultimately exiting via perivenous spaces. This review focuses on important questions about structure this system, why needs transport unexplored aspects transport. We provide evidence that astrocytes blood vessels determine shape perivascular space, controlling fluid. Glymphatic has potential to alter local as well global signaling molecules metabolites. also highlight for cross talk among cardiovascular gastrointestinal tract, system. Much remains be studied, but we propose glymphatic/lymphatic acts cornerstone between body.

Язык: Английский

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