Cerebral blood flow is reduced early in the onset of Alzheimer's disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of ...contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish disease relevance, and rodent experiments to define mechanism. We found that in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ET
receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.
What is a pericyte? Attwell, David; Mishra, Anusha; Hall, Catherine N ...
Journal of cerebral blood flow and metabolism,
02/2016, Letnik:
36, Številka:
2
Journal Article
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Pericytes, spatially isolated contractile cells on capillaries, have been reported to control cerebral blood flow physiologically, and to limit blood flow after ischaemia by constricting capillaries ...and then dying. Paradoxically, a recent paper dismisses the idea of pericytes controlling cerebral blood flow, despite confirming earlier data showing a role for pericytes. We show that these discrepancies are apparent rather than real, and depend on the new paper defining pericytes differently from previous reports. An objective definition of different sub-classes of pericyte along the capillary bed is needed to develop novel therapeutic approaches for stroke and disorders caused by pericyte malfunction.
High-throughput single-cell epigenomic assays can resolve cell type heterogeneity in complex tissues, however, spatial orientation is lost. Here, we present single-cell combinatorial indexing on ...Microbiopsies Assigned to Positions for the Assay for Transposase Accessible Chromatin, or sciMAP-ATAC, as a method for highly scalable, spatially resolved, single-cell profiling of chromatin states. sciMAP-ATAC produces data of equivalent quality to non-spatial sci-ATAC and retains the positional information of each cell within a 214 micron cubic region, with up to hundreds of tracked positions in a single experiment. We apply sciMAP-ATAC to assess cortical lamination in the adult mouse primary somatosensory cortex and in the human primary visual cortex, where we produce spatial trajectories and integrate our data with non-spatial single-nucleus RNA and other chromatin accessibility single-cell datasets. Finally, we characterize the spatially progressive nature of cerebral ischemic infarction in the mouse brain using a model of transient middle cerebral artery occlusion.
Neurovascular coupling is a crucial mechanism that matches the high energy demand of the brain with a supply of energy substrates from the blood. Signaling within the neurovascular unit is ...responsible for activity-dependent changes in cerebral blood flow. The strength and reliability of neurovascular coupling form the basis of non-invasive human neuroimaging techniques, including blood oxygen level dependent (BOLD) functional magnetic resonance imaging. Interestingly, BOLD signals are negative in infants, indicating a mismatch between metabolism and blood flow upon neural activation; this response is the opposite of that observed in healthy adults where activity evokes a large oversupply of blood flow. Negative neurovascular coupling has also been observed in rodents at early postnatal stages, further implying that this is a process that matures during development. This rationale is consistent with the morphological maturation of the neurovascular unit, which occurs over a similar time frame. While neurons differentiate before birth, astrocytes differentiate postnatally in rodents and the maturation of their complex morphology during the first few weeks of life links them with synapses and the vasculature. The vascular network is also incomplete in neonates and matures in parallel with astrocytes. Here, we review the timeline of the structural maturation of the neurovascular unit with special emphasis on astrocytes and the vascular tree and what it implies for functional maturation of neurovascular coupling. We also discuss similarities between immature astrocytes during development and reactive astrocytes in disease, which are relevant to neurovascular coupling. Finally, we close by pointing out current gaps in knowledge that must be addressed to fully elucidate the mechanisms underlying neurovascular coupling maturation, with the expectation that this may also clarify astrocyte-dependent mechanisms of cerebrovascular impairment in neurodegenerative conditions in which reduced or negative neurovascular coupling is noted, such as stroke and Alzheimer's disease.
The neurovascular unit, consisting of neurons, astrocytes, and vascular cells, has become the focus of much discussion in the last two decades and emerging literature now suggests an association ...between neurovascular dysfunction and neurological disorders. In this review, we synthesize the known and suspected contributions of astrocytes to neurovascular dysfunction in disease. Throughout the brain, astrocytes are centrally positioned to dynamically mediate interactions between neurons and the cerebral vasculature, and play key roles in blood-brain barrier maintenance and neurovascular coupling. It is increasingly apparent that the changes in astrocytes in response to a variety of insults to brain tissue –collectively referred to as “reactive astrogliosis” – are not just an epiphenomenon restricted to morphological alterations, but comprise functional changes in astrocytes that contribute to the phenotype of neurological diseases with both beneficial and detrimental effects. In the context of the neurovascular unit, astrocyte dysfunction accompanies, and may contribute to, blood-brain barrier impairment and neurovascular dysregulation, highlighting the need to determine the exact nature of the relationship between astrocyte dysfunction and neurovascular impairments. Targeting astrocytes may represent a new strategy in combinatorial therapeutics for preventing the mismatch of energy supply and demand that often accompanies neurological disorders.
•Astrocytes are centrally positioned to regulate the blood-brain barrier, cerebral blood flow, and neurovascular coupling•In reactive astrogliosis, astrocyte mediation of these processes may be impaired.•Astrocyte dysfunction and the resultant cerebrovascular impairments may be a primary contributor to neuronal dysfunction.•Therapies that protect neurons in isolation while ignoring their glial and vascular context may be intrinsically limited.
Astrocytes are the most common glial cells in the brain with fine processes and endfeet that intimately contact both neuronal synapses and the cerebral vasculature. They play an important role in ...mediating neurovascular coupling (NVC) via several astrocytic Ca2+‐dependent signalling pathways such as K+ release through BK channels, and the production and release of arachidonic acid metabolites. They are also involved in maintaining the resting tone of the cerebral vessels by releasing ATP and COX‐1 derivatives. Evidence also supports a role for astrocytes in maintaining blood pressure‐dependent change in cerebrovascular tone, and perhaps also in blood vessel‐to‐neuron signalling as posited by the ‘hemo‐neural hypothesis’. Thus, astrocytes are emerging as new stars in preserving the intricate balance between the high energy demand of active neurons and the supply of oxygen and nutrients from the blood by maintaining both resting blood flow and activity‐evoked changes therein. Following neuropathology, astrocytes become reactive and many of their key signalling mechanisms are altered, including those involved in NVC. Furthermore, as they can respond to changes in vascular pressure, cardiovascular diseases might exert previously unknown effects on the central nervous system by altering astrocyte function. This review discusses the role of astrocytes in neurovascular signalling in both physiology and pathology, and the impact of these findings on understanding BOLD‐fMRI signals.
Putative signalling pathways between neurons, astrocytes and the vasculature.
Neurovascular coupling is a process through which neuronal activity leads to local increases in blood flow in the central nervous system. In brain slices, 100% O2 has been shown to alter ...neurovascular coupling, suppressing activity-dependent vasodilation. However, in vivo, hyperoxia reportedly has no effect on blood flow. Resolving these conflicting findings is important, given that hyperoxia is often used in the clinic in the treatment of both adults and neonates, and a reduction in neurovascular coupling could deprive active neurons of adequate nutrients. Here we address this issue by examining neurovascular coupling in both ex vivo and in vivo rat retina preparations. In the ex vivo retina, 100% O2 reduced light-evoked arteriole vasodilations by 3.9-fold and increased vasoconstrictions by 2.6-fold. In vivo, however, hyperoxia had no effect on light-evoked arteriole dilations or blood velocity. Oxygen electrode measurements showed that 100% O2 raised pO2 in the ex vivo retina from 34 to 548 mm Hg, whereas hyperoxia has been reported to increase retinal pO2 in vivo to only ∼53 mm Hg Yu DY, Cringle SJ, Alder VA, Su EN (1994) Am J Physiol 267:H2498-H2507. Replicating the hyperoxic in vivo pO2 of 53 mm Hg in the ex vivo retina did not alter vasomotor responses, indicating that although O2 can modulate neurovascular coupling when raised sufficiently high, the hyperoxia-induced rise in retinal pO2 in vivo is not sufficient to produce a modulatory effect. Our findings demonstrate that hyperoxia does not alter neurovascular coupling in vivo, ensuring that active neurons receive an adequate supply of nutrients.
•The current review covers in detail raw materials that are used in the development of vegan meat flavour.•Various techniques, methods and reactions that are involved in the formation of flavours in ...the final product has been extensively discussed in the current review.•Challenges involved in the development of vegan based meat flavour have also been stated.
The inclination towards naturalness and "clean label" products amongst the consumers has encouraged the development of novel processes for the production of vegan meat flavour. Many basic investigations indicate that acid, enzymatic, or fermentation reactions can be used to produce specific flavour molecules or more complicated flavour formulations. This review summarises recent basic research and development on meat flavour by using different vegan sources. The combination of acid or enzymatic treatment or fermentation of raw materials with heat-induced food processes (e.g., extrusion) represents an elegant approach for generating meat flavour. The current review illustrates the different raw materials, techniques, and challenges in producing vegan meat flavour.
Cerebral blood flow increases in regions of increased brain activity. In this issue of Neuron, Rungta et al. (2018) characterize the contribution of different vascular compartments in generating this ...increase and outline the time course of arteriole and capillary dilation in generating functional hyperemia.
Cerebral blood flow increases in regions of increased brain activity. In this issue of Neuron, Rungta et al. (2018) characterize the contribution of different vascular compartments in generating this increase and outline the time course of arteriole and capillary dilation in generating functional hyperemia.
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