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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 ability of transplanted neural stem cells to ameliorate neuropathological and behavioral phenotypes after experimental stroke in mice is enhanced by co-treatment with 3K3A-APC, which acts to stimulate neuronal differentiation and functional integration within the host circuitry. Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage 1 . Recombinant variants of APC, such as the 3K3A-APC (Lys191–193Ala) mutant in which three Lys residues (KKK191–193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke 2 , 3 , 4 , 5 , 6 , brain trauma 7 , multiple sclerosis 8 , amyotrophic lateral sclerosis 9 , sepsis 10 , 11 , ischemic and reperfusion injury of heart 12 , kidney and liver 13 , pulmonary, kidney and gastrointestinal inflammation 1 , 11 , diabetes 14 and lethal body radiation 15 . On the basis of proof-of-concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke 16 , 17 . Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro 18 via a PAR1–PAR3–sphingosine-1-phosphate-receptor 1–Akt pathway 19 , which suggests the potential for APC-based treatment as a strategy for structural repair in the human central nervous (CNS) system. Here we report that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs might offer a new approach to the treatment of stroke and related neurological disorders.

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.

Targeting immune-mediated, age-related, biology has the potential to be a transformative therapeutic strategy. However, the redundant nature of the multiple cytokines that change with aging requires identification of a master downstream regulator to successfully exert therapeutic efficacy. Here, we discovered CCR3 as a prime candidate, and inhibition of CCR3 has pro-cognitive benefits in mice, but these benefits are not driven by an obvious direct action on central nervous system (CNS)-resident cells. Instead, CCR3-expressing T cells in the periphery that are modulated in aging inhibit infiltration of these T cells across the blood-brain barrier and reduce neuroinflammation. The axis of CCR3-expressing T cells influencing crosstalk from periphery to brain provides a therapeutically tractable link. These findings indicate the broad therapeutic potential of CCR3 inhibition in a spectrum of neuroinflammatory diseases of aging. CCR3 is shown to play a role in age-related T cell infiltration into the brain in mice as well as age-related changes in cognition, highlighting its therapeutic potential for age-related diseases.

Introduction Increasing age is the number one risk factor for developing cognitive decline and neurodegenerative disease. Aged humans and mice exhibit numerous molecular changes that contribute to a decline in cognitive function and increased risk of developing age‐associated diseases. Here, we characterize multiple age‐associated changes in male C57BL/6J mice to understand the translational utility of mouse aging. Methods Male C57BL/6J mice from various ages between 2 and 24 months of age were used to assess behavioral, as well as, histological and molecular changes across three modalities: neuronal, microgliosis/neuroinflammation, and the neurovascular unit (NVU). Additionally, a cohort of 4‐ and 22‐month‐old mice was used to assess blood‐brain barrier (BBB) breakdown. Mice in this cohort were treated with a high, acute dose of lipopolysaccharide (LPS, 10 mg/kg) or saline control 6 h prior to sacrifice followed by tail vein injection of 0.4 kDa sodium fluorescein (100 mg/kg) 2 h later. Results Aged mice showed a decline in cognitive and motor abilities alongside decreased neurogenesis, proliferation, and synapse density. Further, neuroinflammation and circulating proinflammatory cytokines were increased in aged mice. Additionally, we found changes at the BBB, including increased T cell infiltration in multiple brain regions and an exacerbation in BBB leakiness following chemical insult with age. There were also a number of readouts that were unchanged with age and have limited utility as markers of aging in male C57BL/6J mice. Conclusions Here we propose that these changes may be used as molecular and histological readouts that correspond to aging‐related behavioral decline. These comprehensive findings, in the context of the published literature, are an important resource toward deepening our understanding of normal aging and provide an important tool for studying aging in mice. We identify robust molecular and histological changes with age in male C57BL/6J mice that may be used as correlates of aging‐related cognitive decline. These comprehensive findings, in the context of the published literature, are an important resource towards deepening our understanding of normal aging and provide an important tool for studying aging in mice.

Zhao et al . report that brain vessels have a major role in clearing Alzheimer's disease–related toxin Aβ from brain and show that PICALM gene product and its variant associated with an increased risk for Alzheimer's disease inactivate an Aβ clearance system in blood vessels, leading to Aβ brain accumulation and cognitive impairment. PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aβ clearance across the murine blood-brain barrier (BBB) and accelerated Aβ pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Aβ bound to the low density lipoprotein receptor related protein-1, a key Aβ clearance receptor, and guided Aβ trafficking to Rab5 and Rab11, leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell–derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance, which has implications for Aβ brain homeostasis and clearance therapy.

Apolipoprotein E4 ( APOE4 ), the main susceptibility gene for Alzheimer’s disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood–brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer’s mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD. This study shows that APOE4, one of the largest genetic risk factors for Alzheimer’s disease, promotes advanced-stage vascular dysfunction and neurodegeneration in old mice via activation of the cyclophilin A pathway in pericytes and independently of the presence of amyloid-β.

Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by activation of protease-activated receptors 1 and 3 (PAR1, PAR3) via non-canonical cleavage1. Recombinant APC and/or its analogs with reduced (>90%) anticoagulant activity such as 3K3A-APC (Lys191–193Ala), engineered to reduce APC-associated bleeding risk while retaining normal cell signaling activity, have shown benefits in preclinical models of ischemic stroke2–6, brain trauma7, multiple sclerosis8, amyotrophic lateral sclerosis9, sepsis10,11, ischemic/reperfusion injury of heart12, kidney and liver13, pulmonary, kidney and gastrointestinal inflammation1,11, diabetes14 and lethal body radiation15. Based on proof of concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke16,17. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem/progenitor cells (NSCs) in vitro18 via a PAR1-PAR3-sphingosine-1-phosphate receptor 1-Akt pathway19, suggesting the potential for APC-based treatment as a strategy for structural repair in the human central nervous system. Here, we report that late post-ischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration, and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs may offer a new approach to the treatment of stroke and related neurological disorders.