Noninvasive Magnetic Resonance Imaging Detection of Cerebral Amyloid Angiopathy-Related Microvascular Alterations Using Superparamagnetic Iron Oxide Particles in APP Transgenic Mouse Models of Alzheimer's Disease: Application to Passive Aβ Immunotherapy

Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer's disease (AD). More advanced stages are accompanied by microhemorrhages and vasculitis. Peripheral blood-borne macrophages are intimately linked to cerebrovascular pathology coincident with AD. Magnetic resonance imaging (MRI) was used to noninvasively study microvascular lesions in amyloid precursor protein transgenic mouse AD models. Foci of signal attenuation were detected in cortical and thalamic brain regions of aged APP23 mice. Their strength and number was considerably enhanced by intravenous administration of iron oxide nanoparticles, which are taken up by macrophages through absorptive endocytosis, 24 h before image acquisition. The number of cortical sites displaying signal attenuation increased with age. Histology at these sites demonstrated the presence of iron-containing macrophages in the vicinity of CAA-affected blood vessels. A fraction of the sites additionally showed thickened vessel walls and vasculitis. Consistent with the visualization of CAA-associated lesions, MRI detected a much smaller number of attenuated signal sites in APP23xPS45 mice, for which a strong presenilin mutation caused a shift toward amyloid β42, thus reducing vascular amyloid. Similar results were obtained with APP24 and APP51 mice, which develop significantly less CAA and microvascular pathology than APP23. In a longitudinal study, we noninvasively demonstrated the reinforced formation of microvascular pathology during passive amyloid β immunotherapy of APP23 mice. Histology confirmed that foci of signal attenuation reflected an increase in CAA-related lesions. Our data demonstrate that MRI has the sensitivity to noninvasively monitor the development of vascular pathology and its possible enhancement by amyloid β immunotherapy in transgenic mice modeling AD.

[1]  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.

[2]  R O Weller,et al.  Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. , 2008, Brain : a journal of neurology.

[3]  R. Roos,et al.  Secondary microvascular degeneration in amyloid angiopathy of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) , 1998, Acta Neuropathologica.

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

[5]  Philippe Robert,et al.  Comparison of Different Types of Blood Pool Agents (P792, MS325, USPIO) in a Rabbit MR Angiography-like Protocol , 2003, Investigative radiology.

[6]  M. Staufenbiel,et al.  Amyloid precursor protein truncated at any of the gamma-secretase sites is not cleaved to beta-amyloid. , 1996, Journal of neuroscience research.

[7]  M. Staufenbiel,et al.  Amyloid precursor protein truncated at any of the γ‐secretase sites is not cleaved to β‐amyloid , 1996 .

[8]  M. Staufenbiel,et al.  Vessel ultrastructure in APP23 transgenic mice after passive anti-Aβ immunotherapy and subsequent intracerebral hemorrhage , 2007, Neurobiology of Aging.

[9]  M. Staufenbiel,et al.  Cerebral Hemorrhage After Passive Anti-Aβ Immunotherapy , 2002, Science.

[10]  Markus Rudin,et al.  Age-Dependent Impairment of Somatosensory Response in the Amyloid Precursor Protein 23 Transgenic Mouse Model of Alzheimer's Disease , 2003, The Journal of Neuroscience.

[11]  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.

[12]  R. Roos,et al.  Association of Vascular Amyloid β and Cells of the Mononuclear Phagocyte System in Hereditary Cerebral Hemorrhage with Amyloidosis (Dutch) and Alzheimer Disease , 1997, Journal of neuropathology and experimental neurology.

[13]  J. Julien,et al.  Bone Marrow-Derived Microglia Play a Critical Role in Restricting Senile Plaque Formation in Alzheimer's Disease , 2006, Neuron.

[14]  C. Benesch,et al.  Small chronic hemorrhages and ischemic lesions in association with spontaneous intracerebral hematomas. , 1999, Stroke.

[15]  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.

[16]  E Mark Haacke,et al.  Imaging cerebral microbleeds using susceptibility weighted imaging: One step toward detecting vascular dementia , 2010, Journal of magnetic resonance imaging : JMRI.

[17]  Eric E. Smith,et al.  Amyloid Angiopathy–Related Vascular Cognitive Impairment , 2004, Stroke.

[18]  C. W. Jung.  Surface properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil. , 1995, Magnetic resonance imaging.

[19]  M. Weinand,et al.  Amyloid-β Induces Chemokine Secretion and Monocyte Migration across a Human Blood-Brain Barrier Model , 1998, Molecular medicine.

[20]  D. Holtzman,et al.  Active and passive immunotherapy for neurodegenerative disorders. , 2008, Annual review of neuroscience.

[21]  K. Jellinger,et al.  Alzheimer disease and cerebrovascular pathology: an update , 2002, Journal of Neural Transmission.

[22]  Kurt Bürki,et al.  Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis , 2004, Nature Neuroscience.

[23]  M. Frosch,et al.  Course of cerebral amyloid angiopathy–related inflammation , 2007, Neurology.

[24]  J. Wardlaw,et al.  Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. , 2007, Brain : a journal of neurology.

[25]  Dietmar Rudolf Thal,et al.  Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease , 2008, Acta Neuropathologica.

[26]  Arthur Konnerth,et al.  Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer's Disease , 2008, Science.

[27]  M. Staufenbiel,et al.  Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid. , 2002, Journal of neurochemistry.

[28]  C. Geula,et al.  Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease , 2007, Nature Medicine.

[29]  V. Dousset,et al.  In vivo visualization of macrophage infiltration and activity in inflammation using magnetic resonance imaging. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[30]  T. Imaizumi,et al.  Dot‐like Hemosiderin Spots on Gradient Echo T2*‐Weighted Magnetic Resonance Imaging Are Associated With Past History of Small Vessel Disease in Patients With Intracerebral Hemorrhage , 2004, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[31]  M. Graves,et al.  Cyclooxygenase‐2‐positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood–brain barrier , 2002, European journal of clinical investigation.

[32]  S. Hickman,et al.  Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. , 2010, CNS & neurological disorders drug targets.

[33]  P Kapeller,et al.  Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds. , 1999, AJNR. American journal of neuroradiology.

[34]  M. Staufenbiel,et al.  Expression of human β‐secretase in the mouse brain increases the steady‐state level of β‐amyloid , 2002 .

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

[36]  R. Weissleder,et al.  Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. , 1990, Radiology.

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

[38]  M. Stoeckli,et al.  Dynamics of Aβ Turnover and Deposition in Different β-Amyloid Precursor Protein Transgenic Mouse Models Following γ-Secretase Inhibition , 2008, Journal of Pharmacology and Experimental Therapeutics.

[39]  A. Stalder,et al.  Invasion of Hematopoietic Cells into the Brain of Amyloid Precursor Protein Transgenic Mice , 2005, The Journal of Neuroscience.

[40]  D. Wilcock,et al.  Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid. , 2007, Neuroscience.

[41]  Gregory M. Szilagyi,et al.  Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook dementia study. , 2008, Archives of neurology.

[42]  M. Staufenbiel,et al.  Cerebral hemorrhage after passive anti-Abeta immunotherapy. , 2002, Science.