Detection of vascular alterations by in vivo magnetic resonance angiography and histology in APP/PS1 mouse model of Alzheimer’s disease

ObjectThe brain of patients with Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles. Vascular alterations such as amyloid angiopathy are also commonly reported in patients with AD and participate in mechanisms involved in disease onset and progression. Transgenic mouse models of AD have been engineered to evaluate the pathophysiology and new treatments of the disease. Our study evaluated vascular alterations in APPSweLon/PS1M146L mouse model of AD.Materials and methodsHistological analysis and in vivo magnetic resonance angiography protocols based on time of flight (TOF) and contrast-enhanced (CE) angiography were applied to evaluate cerebrovascular alterations.ResultsHistological analysis showed that cerebrovascular amyloid deposition starts by the same time as extracellular amyloid plaques. However, unlike plaques deposition, severity of cerebrovascular alterations is stabilized in older animals. Alteration of the middle cerebral artery was detected in old APPSweLon/PS1M146L mice with respect to adult ones by evaluating the severity of vessel voids and the reduction of vessel length on TOF- and CE-angiograms. Age-related alterations in control PS1 mice were only detected as a reduced vessel length on CE-angiograms.ConclusionThese results show that macroscopic vascular abnormalities are part of the pathological alterations developed by APPSweLon/PS1M146L mouse models of AD.

[1]  M. Port,et al.  P792: a rapid clearance blood pool agent for magnetic resonance imaging: preliminary results , 2001, Magnetic Resonance Materials in Physics, Biology and Medicine.

[2]  D. Mann,et al.  Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease , 2003, Neuroscience Letters.

[3]  Marc Dhenain,et al.  Characterization of in vivo MRI detectable thalamic amyloid plaques from APP/PS1 mice , 2009, Neurobiology of Aging.

[4]  N. Patel,et al.  Proinflammatory and Vasoactive Effects of Aβ in the Cerebrovasculature , 2002, Annals of the New York Academy of Sciences.

[5]  B. Sommer,et al.  Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. C. Torre.  Is Alzheimer's disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics , 2004, The Lancet Neurology.

[7]  Markus Rudin,et al.  Magnetic resonance angiography of the rat cerebrovascular system without the use of contrast agents , 1999, NMR in biomedicine.

[8]  Marc Dhenain,et al.  In vivo MRI and histological evaluation of brain atrophy in APP/PS1 transgenic mice , 2006, Neurobiology of Aging.

[9]  H. Puchtler,et al.  ON THE BINDING OF CONGO RED BY AMYLOID , 1962 .

[10]  T. Bayer,et al.  Reelin in plaques of β-amyloid precursor protein and presenilin-1 double-transgenic mice , 2001, Neuroscience Letters.

[11]  H. Bosmans,et al.  Time-of-flight MR angiography of the brain: comparison of acquisition techniques in healthy volunteers. , 1995, AJR. American journal of roentgenology.

[12]  John G. Sled,et al.  Three-dimensional cerebral vasculature of the CBA mouse brain: A magnetic resonance imaging and micro computed tomography study , 2007, NeuroImage.

[13]  N. Beckmann,et al.  High-resolution magnetic resonance angiography of the mouse brain: application to murine focal cerebral ischemia models. , 1999, Journal of magnetic resonance.

[14]  H. Vinters.  Cerebral amyloid angiopathy. A critical review. , 1987, Stroke.

[15]  David M Holtzman,et al.  Cerebrovascular Dysfunction in Amyloid Precursor Protein Transgenic Mice: Contribution of Soluble and Insoluble Amyloid-β Peptide, Partial Restoration via γ-Secretase Inhibition , 2008, The Journal of Neuroscience.

[16]  Feng He,et al.  Use of Autostitch for automatic stitching of microscope images. , 2007, Micron.

[17]  B. Sommer,et al.  Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Masahito Yamada,et al.  Cerebral amyloid angiopathy: An overview , 2000, Neuropathology : official journal of the Japanese Society of Neuropathology.

[19]  S. Kumar-Singh,et al.  Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques , 2008, Genes, brain, and behavior.

[20]  John Hardy,et al.  Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. , 2005, The American journal of pathology.

[21]  O. Scremin.  CHAPTER 33 – Cerebral Vascular System , 2004 .

[22]  M. Uchiyama,et al.  Latent cerebral artery stenoses on magnetic resonance angiography in a patient diagnosed as probable Alzheimer disease , 1998, Psychiatry and clinical neurosciences.

[23]  H. Tanila,et al.  Longitudinal observation on CSF Aβ42 levels in young to middle-aged amyloid precursor protein/presenilin-1 doubly transgenic mice , 2004, Neurobiology of Disease.

[24]  W. H. Jordan,et al.  Exacerbation of Cerebral Amyloid Angiopathy-Associated Microhemorrhage in Amyloid Precursor Protein Transgenic Mice by Immunotherapy Is Dependent on Antibody Recognition of Deposited Forms of Amyloid β , 2005, The Journal of Neuroscience.

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

[26]  D. Cornfield,et al.  A beta-peptides enhance vasoconstriction in cerebral circulation. , 2001, American journal of physiology. Heart and circulatory physiology.

[27]  Brian J Bacskai,et al.  Progression of Cerebral Amyloid Angiopathy in Transgenic Mouse Models of Alzheimer Disease , 2005, Journal of neuropathology and experimental neurology.

[28]  M. Dhenain,et al.  Transverse relaxation time reflects brain amyloidosis in young APP/PS1 transgenic mice , 2007, Magnetic resonance in medicine.

[29]  Oliver Wirths,et al.  Intraneuronal Aβ accumulation precedes plaque formation in β-amyloid precursor protein and presenilin-1 double-transgenic mice , 2001, Neuroscience Letters.

[30]  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.

[31]  M. Moskowitz,et al.  Structural and functional disruption of vascular smooth muscle cells in a transgenic mouse model of amyloid angiopathy. , 2001, The American journal of pathology.

[32]  D. Cornfield,et al.  Aβ-peptides enhance vasoconstriction in cerebral circulation , 2001 .

[33]  D. Royall,et al.  Alzheimer disease as a vascular disorder: nosological evidence. , 2002, Stroke.

[34]  D. Selkoe,et al.  Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior , 2008, Behavioural Brain Research.

[35]  Thomas Krucker,et al.  Age-Dependent Cerebrovascular Abnormalities and Blood Flow Disturbances in APP23 Mice Modeling Alzheimer's Disease , 2003, The Journal of Neuroscience.

[36]  G. Higgins,et al.  Transgenic mouse models of Alzheimer's disease: phenotype and application , 2003, Behavioural pharmacology.

[37]  F Fazio,et al.  Correlations between cognitive impairment, middle cerebral artery flow velocity and cortical glucose metabolism in the early phase of Alzheimer's disease. , 1995, Dementia.

[38]  N. Beckmann,et al.  High resolution magnetic resonance angiography non‐invasively reveals mouse strain differences in the cerebrovascular anatomy in vivo , 2000, Magnetic resonance in medicine.

[39]  T. Bayer,et al.  Time sequence of maturation of dystrophic neurites associated with Aβ deposits in APP/PS1 transgenic mice , 2003, Experimental Neurology.

[40]  M. Prince.  Gadolinium-enhanced MR aortography. , 1990, Radiology.

[41]  Thomas Krucker,et al.  Magnetic resonance angiography and vascular corrosion casting as tools in biomedical research: application to transgenic mice modeling Alzheimer's disease , 2004, Neurological research.

[42]  C. Iadecola,et al.  Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. , 2002, American journal of physiology. Heart and circulatory physiology.

[43]  Marc Dhenain,et al.  Age-related evolution of amyloid burden, iron load, and MR relaxation times in a transgenic mouse model of Alzheimer's disease , 2006, Neurobiology of Disease.

[44]  Brian J. Bacskai,et al.  Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease , 2006, Neurobiology of Disease.

[45]  Yu-Min Kuo,et al.  Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. , 1998, The American journal of pathology.

[46]  S. Confort-Gouny,et al.  Imaging Experimental Cerebral Malaria In Vivo: Significant Role of Ischemic Brain Edema , 2005, The Journal of Neuroscience.

[47]  J Shi,et al.  Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer's disease , 2004, Neuropathology and applied neurobiology.

[48]  R. Weller,et al.  Cerebral amyloid angiopathy: Pathogenesis and effects on the ageing and Alzheimer brain , 2003, Neurological research.

[49]  C. Duyckaerts,et al.  Alzheimer disease models and human neuropathology: similarities and differences , 2007, Acta Neuropathologica.

[50]  T. Thomas,et al.  beta-Amyloid induces cerebrovascular endothelial dysfunction in the rat brain. , 1997, Neurological research.

[51]  A. Foundas,et al.  The Cerebral Vascular System , 2008 .

[52]  Thomas Krucker,et al.  Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease , 2008, Proceedings of the National Academy of Sciences.

[53]  M. Staufenbiel,et al.  Spontaneous Hemorrhagic Stroke in a Mouse Model of Cerebral Amyloid Angiopathy , 2001, The Journal of Neuroscience.

[54]  Dietmar Rudolf Thal,et al.  Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances , 2009, Neurobiology of Aging.

[55]  T. Bayer,et al.  Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. , 2001, Neuroscience letters.