Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer’s disease

INTRODUCTION In this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD. METHODS We inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels. RESULTS We found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways. DISCUSSION Oxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

[1]  T. Shekh-Ahmad,et al.  Specific inhibition of NADPH oxidase 2 modifies chronic epilepsy , 2022, Redox biology.

[2]  D. Drachman,et al.  Cumulative effect of simvastatin, l-arginine, and tetrahydrobiopterin on cerebral blood flow and cognitive function in Alzheimer’s disease , 2022, Alzheimer's Research & Therapy.

[3]  K. Arai,et al.  Effects of cerebral amyloid angiopathy on the brain vasculome , 2022, Aging cell.

[4]  A. Fagan,et al.  Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease , 2022, Neurology: Neuroimmunology & Neuroinflammation.

[5]  N. Nishimura,et al.  VEGF signalling causes stalls in brain capillaries and reduces cerebral blood flow in Alzheimer’s mice , 2022, Brain : a journal of neurology.

[6]  A. Hainsworth,et al.  Vascular cognitive impairment and dementia: An early career researcher perspective , 2022, Alzheimer's & dementia.

[7]  C. Iadecola,et al.  Revisiting the neurovascular unit , 2021, Nature Neuroscience.

[8]  Y. Kulkarni,et al.  Pharmacology of apocynin: a natural acetophenone , 2021, Drug metabolism reviews.

[9]  H. Potter,et al.  Astrogliosis and episodic memory in late life: higher GFAP is related to worse memory and white matter microstructure in healthy aging and Alzheimer's disease , 2021, Neurobiology of Aging.

[10]  K. Blennow,et al.  Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer’s disease , 2020, Translational Psychiatry.

[11]  David A Hartmann,et al.  Brain capillary pericytes exert a substantial but slow influence on blood flow , 2020, Nature Neuroscience.

[12]  Nancy Ruiz-Uribe,et al.  Brain and blood extraction for immunostaining, protein, and RNA measurements after long-term two photon imaging in mice. , 2020 .

[13]  Yun-Kyoung Lee,et al.  The isolation and molecular characterization of cerebral microvessels , 2019, Nature Protocols.

[14]  G. Douglas,et al.  Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature , 2019, The Journal of clinical investigation.

[15]  D. Attwell,et al.  Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes , 2019, Science.

[16]  R. Kievit,et al.  MICROGLIAL ACTIVATION AND TAU BURDEN PREDICT COGNITIVE DECLINE IN ALZHEIMER’S DISEASE , 2019, Alzheimer's & Dementia.

[17]  Chris B. Schaffer,et al.  Increasing cerebral blood flow improves cognition into late stages in Alzheimer’s disease mice , 2019, bioRxiv.

[18]  S. Quake,et al.  Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1 , 2019, Nature Medicine.

[19]  John X. Morris,et al.  Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction , 2018, Nature Medicine.

[20]  Myriam Peyrounette,et al.  Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models , 2018, Nature Neuroscience.

[21]  T. Deierborg,et al.  Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response , 2018, Front. Cell. Neurosci..

[22]  Eun Woo Son,et al.  iDEP: an integrated web application for differential expression and pathway analysis of RNA-Seq data , 2018, BMC Bioinformatics.

[23]  C. Claudianos,et al.  Brain Energy and Oxygen Metabolism: Emerging Role in Normal Function and Disease , 2018, Front. Mol. Neurosci..

[24]  Ya-Ting Chang,et al.  Cerebral Perfusion Insufficiency and Relationships with Cognitive Deficits in Alzheimer’s Disease: A Multiparametric Neuroimaging Study , 2018, Scientific Reports.

[25]  Arne Møller,et al.  Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease , 2017, Alzheimer's & Dementia.

[26]  Axel Montagne,et al.  Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease , 2017, Nature Reviews Neuroscience.

[27]  A. Heerschap,et al.  Hypertension, cerebrovascular impairment, and cognitive decline in aged AβPP/PS1 mice , 2017, Theranostics.

[28]  S. Cuzzocrea,et al.  FeTPPS Reduces Secondary Damage and Improves Neurobehavioral Functions after Traumatic Brain Injury , 2017, Front. Neurosci..

[29]  B. Stoica,et al.  Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury. , 2016, Journal of neurotrauma.

[30]  Gary D. Bader,et al.  AutoAnnotate: A Cytoscape app for summarizing networks with semantic annotations , 2016, F1000Research.

[31]  Norbert Schuff,et al.  Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis , 2016, Nature Communications.

[32]  G. Wang,et al.  Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations , 2016, Cellular and Molecular Neurobiology.

[33]  D. Catalucci,et al.  Neutrophils promote Alzheimer's disease–like pathology and cognitive decline via LFA-1 integrin , 2015, Nature Medicine.

[34]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[35]  C. Iadecola,et al.  The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction , 2014, Nature Communications.

[36]  Norbert Schuff,et al.  Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment. , 2014, Brain : a journal of neurology.

[37]  D. Attwell,et al.  Capillary pericytes regulate cerebral blood flow in health and disease , 2014, Nature.

[38]  Alin Ciobica,et al.  The oxidative stress hypothesis in Alzheimer's disease. , 2013, Psychiatria Danubina.

[39]  C. Iadecola,et al.  The Pathobiology of Vascular Dementia , 2013, Neuron.

[40]  B. Winblad,et al.  Diabetes, Alzheimer disease, and vascular dementia A population-based neuropathologic study , 2013 .

[41]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[42]  Sung-Ho Han,et al.  Dynamic Optical Imaging of Metabolic and NADPH Oxidase-Derived Superoxide in Live Mouse Brain Using Fluorescence Lifetime Unmixing , 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  M. Beal,et al.  Neuroprotective strategies involving ROS in Alzheimer disease. , 2011, Free radical biology & medicine.

[44]  Marcel Martin.  Cutadapt removes adapter sequences from high-throughput sequencing reads , 2011 .

[45]  C. Iadecola,et al.  Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-β , 2011, Proceedings of the National Academy of Sciences.

[46]  D. Attwell,et al.  Glial and neuronal control of brain blood flow , 2022 .

[47]  J. C. de la Torre.  Vascular risk factor detection and control may prevent Alzheimer's disease. , 2010, Ageing research reviews.

[48]  M. Kivipelto,et al.  Epidemiology of Alzheimer's disease: occurrence, determinants, and strategies toward intervention , 2009, Dialogues in clinical neuroscience.

[49]  C. Szabó,et al.  Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. , 2008, The American journal of pathology.

[50]  Ping Zhou,et al.  Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein , 2008, Proceedings of the National Academy of Sciences.

[51]  Shi-Jiang Li,et al.  Perfusion fMRI detects deficits in regional CBF during memory-encoding tasks in MCI subjects , 2007, Neurology.

[52]  K. Baer,et al.  Immunohistochemical staining of post-mortem adult human brain sections , 2006, Nature Protocols.

[53]  C. Iadecola,et al.  Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. , 2006, Journal of applied physiology.

[54]  Houeto Jean-Luc.  [Parkinson's disease]. , 2022, La Revue du praticien.

[55]  S. Koh,et al.  Effect of 3-aminobenzamide, PARP inhibitor, on matrix metalloproteinase-9 level in plasma and brain of ischemic stroke model. , 2005, Toxicology.

[56]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Xunbin Wei,et al.  In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment , 2005, Nature.

[58]  Ping Zhou,et al.  NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. , 2005, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[59]  B. Hyman,et al.  Imaging Aβ Plaques in Living Transgenic Mice with Multiphoton Microscopy and Methoxy‐X04, a Systemically Administered Congo Red Derivative , 2002, Journal of neuropathology and experimental neurology.

[60]  F. Rey,et al.  Novel Competitive Inhibitor of NAD(P)H Oxidase Assembly Attenuates Vascular O2− and Systolic Blood Pressure in Mice , 2001, Circulation research.

[61]  C. Iadecola,et al.  Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[62]  D. Borchelt,et al.  SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein , 1999, Nature Neuroscience.

[63]  Jack C. de la Torre,et al.  Cerebromicrovascular Pathology in Alzheimer’s Disease Compared to Normal Aging , 1997 .

[64]  W R Markesbery,et al.  Oxidative stress hypothesis in Alzheimer's disease. , 1997, Free radical biology & medicine.