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Key Points Here, we review literature determining the arterial and arteriolar component of cerebral blood flow regulation. Furthermore, we describe evidence of arterial and arteriolar blood flow control by vascular smooth muscle cells (VSMCs), astrocyte-mediated, direct neuron-mediated and endothelium-mediated regulation of VSMC tone. Also, we discuss the capillary component of cerebral blood flow regulation. Importantly, we highlight recent findings regarding the control of capillary blood flow by pericytes, and signalling in astrocytes and pericytes regulating capillary tone. In addition, we examine vascular dysfunction in animal models, including amyloid-β-independent vascular changes, amyloid-β-dependent vascular changes and combined amyloid-β and vascular models. Last, we emphasize Alzheimer disease vascular dysfunction, including cerebrovascular reactivity, cerebral blood flow reductions and neurovascular uncoupling. Cerebral blood flow regulation is essential for normal brain function. In this Review, Kisler and colleagues examine the cellular and molecular mechanisms that underlie cerebral blood flow regulation at the arteriole and capillary level, and how neurovascular dysfunction contributes to neurodegenerative disorders such as Alzheimer disease. Cerebral blood flow (CBF) regulation is essential for normal brain function. The mammalian brain has evolved a unique mechanism for CBF control known as neurovascular coupling. This mechanism ensures a rapid increase in the rate of CBF and oxygen delivery to activated brain structures. The neurovascular unit is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia, and regulates neurovascular coupling. This Review article examines the cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurovascular dysfunction in neurodegenerative disorders such as Alzheimer disease.

Flaviviruses comprise a genus of enveloped, positive-sense, single-stranded RNA viruses typically transmitted between susceptible and permissive hosts by arthropod vectors. Established flavivirus threats include dengue viruses (DENV), yellow fever virus (YFV), Zika virus (ZIKV), and West Nile virus (WNV), which continue to cause over 400 million infections annually and are significant global health and economic burdens. Additionally, numerous closely related but largely understudied viruses circulate in animals and can conceivably emerge in human populations. Previous flaviviruses that were recognized to have this potential include ZIKV and WNV, which only became extensively studied after causing major outbreaks in humans. More than 50 species exist within the flavivirus genus, which can be further classified as mosquito-borne, tick-borne, insect-specific, or with no known vector. Historically, many of these flaviviruses originated in Africa and have mainly affected tropical and subtropical regions due to the ecological niche of mosquitoes. However, climate change, as well as vector and host migration, has contributed to geographical expansion, thereby posing a potential risk to global populations. For the purposes of this minireview, we focus on the mosquito-borne subgroup and highlight viruses that cause significant pathology or lethality in at least one animal species and/or have demonstrated an ability to infect humans. We discuss current knowledge of these viruses, existing animal models to study their pathogenesis, and potential future directions. Emerging viruses discussed include Usutu virus (USUV), Wesselsbron virus (WSLV), Spondweni virus (SPOV), Ilheus virus (ILHV), Rocio virus (ROCV), Murray Valley encephalitis virus (MVEV), and Alfuy virus (ALFV).

Contemporary clinical management relies on a diagnostic label as the primary guide to treatment. However, individual patients’ lived experiences vary more widely than standard diagnostic categories reflect. This is especially true for functional bowel disorders (FBDs), a heterogeneous and challenging group of syndromes where no definitive diagnostic tests, clinical biomarkers, or universally effective treatments exist. Characterising the link between disease and lived experience - in the face of marked patient heterogeneity - requires deep phenotyping of the interactions between multiple characteristics, plausibly achievable only with complex modelling approaches. In a large patient cohort ( n  = 1175), we developed a machine learning and Bayesian generative graph framework to better understand the lived experience of FBDs. Iterating through 59 factors available from routine clinical care, spanning patient demography, diagnosis, symptomatology, life impact, mental health indices, healthcare access requirements, COVID-19 impact, and treatment effectiveness, machine models were used to quantify the predictive fidelity of one feature from the remainder. Bayesian stochastic block models were used to delineate the network community structure underpinning the heterogeneous lived experience of FBDs. Machine models quantified patient personal health rating (R 2 0.35), anxiety and depression severity (R 2 0.54), employment status (balanced accuracy 96%), frequency of healthcare attendance (R 2 0.71), and patient-reported treatment effectiveness variably (R 2 range 0.08–0.41). Contrary to the view of many healthcare professionals, the greatest model predictors of patient-reported health and quality of life were life impact, mental well-being, employment status, and age, rather than diagnostic group or symptom severity. Patients responsive to one treatment were more likely to respond to another, leaving many others refractory to all. Clinical assessment of patients with FBDs should be less concerned with diagnostic classification than with the wider life impact of illness, including mental health and employment. The stratification of treatment response (and resistance) has implications for clinical practice and trial design, necessitating further research.

Winkler et al . show that the glucose transporter GLUT1 in brain endothelium is necessary for the maintenance of proper brain capillary networks and blood-brain barrier integrity. The study also shows that loss of GLUT1 in a mouse model of Alzheimer's disease accelerates BBB breakdown, perfusion and metabolic stress resulting in behavioral deficits, elevated amyloid beta levels and neurodegeneration. The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimer's disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid β-peptide (Aβ) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid β-peptide (Aβ) pathology, reduced Aβ clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimer's disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimer's disease vasculo-neuronal dysfunction and degeneration.

The role of pericytes in the regulation of cerebral blood flow (CBF) and neurovascular coupling remains unclear. Using loss-of-function pericyte-deficient mice, the authors report that pericyte degeneration reduces CBF responses to neuronal stimuli and oxygen supply to the brain, leading to metabolic stress, neuronal dysfunction and neurodegeneration. Pericytes are perivascular mural cells of brain capillaries. They are positioned centrally in the neurovascular unit between endothelial cells, astrocytes and neurons. This position allows them to regulate key neurovascular functions of the brain. The role of pericytes in the regulation of cerebral blood flow (CBF) and neurovascular coupling remains, however, under debate. Using loss-of-function pericyte-deficient mice, here we show that pericyte degeneration diminishes global and individual capillary CBF responses to neuronal stimuli, resulting in neurovascular uncoupling, reduced oxygen supply to the brain and metabolic stress. Neurovascular deficits lead over time to impaired neuronal excitability and neurodegenerative changes. Thus, pericyte degeneration as seen in neurological disorders such as Alzheimer's disease may contribute to neurovascular dysfunction and neurodegeneration associated with human disease.

Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized 1 – 6 . Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction 7 , including the early clinical stages of Alzheimer’s disease 5 , 8 – 10 . The E4 variant of apolipoprotein E ( APOE4 ), the main susceptibility gene for Alzheimer’s disease 11 – 14 , leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes 15 – 19 , which maintain BBB integrity 20 – 22 . It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography 23 . High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ 7 , 8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway 19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4 -associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers. Breakdown of the blood–brain barrier in individuals carrying the ε4 allele of the APOE gene, but not the ε3 allele, increases with and predicts cognitive impairment and is independent of amyloid β or tau pathology.

Vascular contributions to cognitive impairment are increasingly recognized1–5 as shown by neuropathological6,7, neuroimaging4,8–11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer’s disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood–brain barrier (BBB) breakdown14–16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8–10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8–10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer’s Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.Neuroimaging and cerebrospinal fluid analyses in humans reveal that loss of blood–brain barrier integrity and brain capillary pericyte damage are early biomarkers of cognitive impairment that occur independently of changes in amyloid-β and tau.

Usutu virus (USUV) is an emerging mosquito-borne flavivirus known to induce neuroinvasive disease in birds, mice, and humans in European and African countries. The mechanisms of infection and dissemination remain poorly understood. Thus, elucidating how USUV spreads in a susceptible host is crucial for identifying therapeutic targets. To investigate host defenses against USUV, we generated an infectious clone of the TC508 isolate. After characterizing its replication dynamics in cultured cells from multiple species, we investigated its pathogenesis in an array of mice with genetic perturbations. Previous studies demonstrated that whole-body deletion of type I interferon (IFN) signaling led to widespread USUV infection and fatality in mice. Here, we observed the same lethal phenotype in STAT1-deficient mice and identified hematopoietic cells specifically as central to USUV pathogenesis in a mammalian host. Deletion of STAT1 in all hematopoietic subsets, but not hepatocytes, neurons, macrophages or conventional dendritic cells, was sufficient for systemic viral dissemination and ultimate fatality. Conversely, mice lacking functional B, T, and natural killer (NK) cells but with intact myeloid cells were resistant to USUV. Our findings provide new insights into the tissue-specific barriers that regulate USUV infection and underscore the importance of innate immunity in host defense for this important emerging flavivirus.

Brains depend on blood flow for the delivery of oxygen and nutrients essential for proper neuronal and synaptic functioning. French physiologist Rouget was the first to describe pericytes in 1873 as regularly arranged longitudinal amoeboid cells on capillaries that have a muscular coat, implying that these are contractile cells that regulate blood flow. Although there have been >30 publications from different groups, including our group, demonstrating that pericytes are contractile cells that can regulate hemodynamic responses in the brain, the role of pericytes in controlling cerebral blood flow (CBF) has not been confirmed by all studies. Moreover, recent studies using different optogenetic models to express light-sensitive channelrhodopsin-2 (ChR2) cation channels in pericytes were not conclusive; one, suggesting that pericytes expressing ChR2 do not contract after light stimulus, and the other, demonstrating contraction of pericytes expressing ChR2 after light stimulus. Since two-photon optogenetics provides a powerful tool to study mechanisms of blood flow regulation at the level of brain capillaries, we re-examined the contractility of brain pericytes using a new optogenetic model developed by crossing our new inducible pericyte-specific CreER mouse line with ChR2 mice. We induced expression of ChR2 in pericytes with tamoxifen, excited ChR2 by 488 nm light, and monitored pericyte contractility, brain capillary diameter changes, and red blood cell (RBC) velocity in aged mice by two-photon microscopy. Excitation of ChR2 resulted in pericyte contraction followed by constriction of the underlying capillary leading to approximately an 8% decrease ( = 0.006) in capillary diameter. ChR2 excitation in pericytes substantially reduced capillary RBC flow by 42% ( = 0.03) during the stimulation period compared to the velocity before stimulation. Our data suggests that pericytes contract and regulate capillary blood flow in the aging mouse brain. By extension, this might have implications for neurological disorders of the aging human brain associated with neurovascular dysfunction and pericyte loss such as stroke and Alzheimer's disease.