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Hemorrhages in the brain are responsible for about 15% of strokes and are particularly difficult to treat. Costantino Iadecola assesses a new clinical study that may change the view of why a common form of hemorrhage, subarachnoid hemorrhage, often leads to death. Massive brain lesions often develop days after the initial event, a dangerous complication previously attributed to vasospasm, narrowing of the arteries. The study suggests that these lesions may instead by caused by neuronal depolarization, extending in waves across the brain. Gregory del Zoppo explores the connection between deposition of toxic amyloid-β peptides in the brain and hemorrhage. He discusses studies suggesting that the peptides inactivate proteins in the blood that can stop hemorrhage.

A recent Nature paper presents findings that highlight brain fibroblasts as dynamic regulators of tissue repair and immunomodulation after injury, with implications for understanding scar formation, function and long-term outcomes of acute brain injuries.

Rodent stroke models are crucial but often invasive and limited in translational relevance. Here, the authors show that magnetic particle delivery creates a reproducible, minimally invasive thrombotic stroke model in awake mice, improving translational potential.

People who carry the gene variant APOE4 are at higher-than-average risk of developing Alzheimer’s disease. It emerges that this variant is linked to defects in the blood–brain barrier and subsequent cognitive decline.

Reductions in brain glucose metabolism have long been associated with Alzheimer's disease. A study now demonstrates that the endothelial glucose transporter GLUT1 is vital for maintaining brain energy metabolism and vascular clearance of amyloid-β.

How blood-borne inflammatory cells cause tissue damage in the brain after ischemic stroke remains elusive. Peroxiredoxins, cytosolic antioxidant proteins vital for redox balance, are released extracellularly from ischemic cells, acting as potent 'danger signals' that activate macrophages and lead to a harmful cytokine response, a new study shows. The findings unveil a new culprit in the delayed phase of ischemic injury and suggest new therapeutic approaches (pages 911–917).

Schaeffer and Iadecola review the anatomical, molecular and functional heterogeneity of the neurovasculature and highlight the coordinated interaction of factors intrinsic and extrinsic to the brain in its dynamic regulation and role in disease.

ApoE4 is a risk factor for Alzheimer’s disease and vascular dementia. We report that in ApoE4 mice perivascular macrophages are the sole source and effectors of the ApoE4 mediating the neurovascular dysfunction, enhanced white matter damage and cognitive impairment.

Cervical lymphatic vessels drain cerebrospinal fluid from the brain. A recent study reveals an aging-related disruption in the pumping action of lymphatic vessels that hampers lymph flow, which may prevent efficient brain clearance of potentially toxic proteins linked to neurodegenerative disease.

Hypertension can lead to cognitive impairment. However, the underlying mechanisms are unclear. Here, the authors show that meningeal T cell-produced interleukin-17 activates border-associated macrophages, affecting neurovascular and cognitive functions in a mouse model of hypertension.

A high-salt diet in mice induces cognitive impairment through a signalling cascade that culminates in increased phosphorylation of tau.

Acute depletion of meningeal lymphatic vessels impairs the clearance of cerebrospinal fluid and brain macromolecules. A new study by Antila et al. shows that amyloid pathology in Alzheimer’s disease is neither improved nor aggravated by genetic expansion or depletion of meningeal lymphatic vessels.

The authors found that white blood cells plug about 2% of capillaries in the brains of Alzheimer’s disease mouse models. When the adhesion of these cells was blocked, cerebral blood flow immediately increased and cognitive performance rapidly improved.

Park et al. demonstrate in tauopathy models that tau disrupts the interaction between neuronal nitric oxide synthase and PSD95, uncoupling glutamatergic synaptic activity from nitric oxide production and dampening the hemodynamic response to activation.

Hardening of the arteries (atherosclerosis) was linked to dementia long ago, but subsequently, Alzheimer’s plaques and tangles have received more attention. A new proteome-wide association study unveils molecular links between intracranial atherosclerosis and dementia, independent of other pathologies, providing new evidence for one of the oldest suspected causes of dementia.

ApoE4 is a risk factor for small vessel disease, which can lead to cognitive impairment. Here the authors assess the microvasculature of the corpus callosum using 3-photon microscopy and find that mice expressing the ApoE4 allele are more susceptible than wild-type to white matter injury and cognitive impairment in a model of hypoperfusion-induced hypoxia.

Migraine sufferers experience pounding headaches, which sometimes are preceded by a visual aura. Now Bolay et al. show that cortical-spreading depression, the cause of the aura, activates trigeminal afferents, which act to cause inflammation of the pain-sensitive meninges, generating the headache. (pages 136–142)

The reduction in blood flow to the brain that causes a stroke triggers a deadly cascade of events that can lead to brain death. Studies in mice show that activation of an adenosine receptor on neutrophils invading the brain from the blood contribute to the damage (pages 1081–1087).

Loss of the transcription factor Gax is at the center of blood vessel dysregulation in the brain and contributes to Alzheimer disease pathology (pages 959–965).

A salt-rich diet promotes cerebrovascular diseases and dementia. This study shows that high dietary salt in mice induces a TH17 response in the gut leading to cerebral endothelial dysfunction and cognitive impairment via circulating IL-17.

Alterations in the gut microbiota affect stroke outcomes via modulation of T cells, suggesting a gut-brain axis linking commensal microbes with the CNS.

Anrather and colleagues provide a longitudinal single-cell transcriptomic atlas of brain and mouse blood following stroke, describing brain-infiltrating leukocytes, circulating leukocytes, microglia and endothelium diversity over the ischemic–reperfusion time

Peripheral organ dysfunction can have considerable effects on brain health, contributing to neurodegeneration and dementia. This Review explores how clinical and subclinical dysfunction of specific organ systems can impact brain health and discusses the implications for dementia prevention.

A great many aspects of neuronal physiology and pathology involve or affect the brain barriers. Recent insights into the role of the blood–brain barrier during development, and advances in our understanding of how it affects neurological disorders, have led to closer links between the two topics.

There remains an urgent need to develop new strategies and therapies to help protect the brain from ischemic cell death. In this perspective, the authors suggest that learning more about the mechanisms that underlie brain self-preservation and developing multifaceted approaches that act on multiple pathways involved in both cell death and neuroprotection may advance our efforts to treat stroke.

This study identifies postsynaptic proteins, many being kinases known to participate in ischemic injury, as major ubiquitination targets after cerebral ischemic stroke. The authors also show that ubiquitination regulates activities of these kinases.

Immunity and inflammation are key elements of the pathobiology of stroke, a devastating illness second only to cardiac ischemia as a cause of death worldwide. The immune system participates in the brain damage produced by ischemia, and the damaged brain, in turn, exerts an immunosuppressive effect that promotes fatal infections that threaten the survival of people after stroke. Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion to the late regenerative processes underlying post-ischemic tissue repair. Recent developments have revealed that stroke engages both innate and adaptive immunity. But adaptive immunity triggered by newly exposed brain antigens does not have an impact on the acute phase of the damage. Nevertheless, modulation of adaptive immunity exerts a remarkable protective effect on the ischemic brain and offers the prospect of new stroke therapies. As immunomodulation is not devoid of deleterious side effects, a better understanding of the reciprocal interaction between the immune system and the ischemic brain is essential to harness the full therapeutic potential of the immunology of stroke.