Mechanisms of Cerebrovascular Amyloid Deposition: Lessons from Mouse Models

Abstract: Cerebrovascular deposition of amyloid is a frequent observation in Alzheimer's disease patients. It can also be detected sporadically in normal aged individuals and is further found in familial diseases linked to specific gene mutations. The source and mechanism of this pathology are still unknown. It has been suggested that amyloidogenic proteins are derived from blood, the vessel wall itself, or from the central nervous system. in this article evidence is reviewed for and against each of these hypotheses, including new data obtained from transgenic mouse models. in app23 transgenic mice that develop cerebral amyloid angiopathy (CAA) in addition to amyloid plaques, the transport and drainage of neuronally produced amyloid‐β (aβ) seem to be responsible for CAA rather than vascular aβ production or blood uptake. although a number of mechanisms may contribute to CAA in humans, these results suggest that a neuronal source of aβ is sufficient to induce vascular amyloid deposition. The possibility to cross genetically defined mouse models of CAA with other mutant mice now has the potential to identify molecular mechanisms of CAA.

[1]  D. D'urso,et al.  Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[2]  L. Walker,et al.  Cystatin C. Icelandic-like mutation in an animal model of cerebrovascular beta-amyloidosis. , 1996, Stroke.

[3]  J. Rhodin,et al.  In vivo vascular damage, leukocyte activation and inflammatory response induced by beta-amyloid. , 1997, Journal of submicroscopic cytology and pathology.

[4]  J. Ghiso,et al.  Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[5]  I. Olafsson,et al.  Structure and expression of the human cystatin C gene. , 1990, The Biochemical journal.

[6]  O. Salonen,et al.  Gelsolin‐related spinal and cerebral amyloid angiopathy , 1999, Annals of neurology.

[7]  A. Aguzzi,et al.  Transgenic and Knockout Mice in Research on Prion Diseases , 1998, Brain pathology.

[8]  J. Gardella,et al.  Characterization of Alzheimer amyloid precursor protein transcripts in platelets and megakarocytes , 1992, Neuroscience Letters.

[9]  K. Campbell,et al.  Dystroglycan in the Cerebellum is a Laminin α2‐chain Binding Protein at the Glial‐Vascular Interface and is Expressed in Purkinje cells , 1996, The European journal of neuroscience.

[10]  C. Cotman,et al.  Amyloid βprotein precursor in cultured leptomeningeal smooth muscle cells , 1994 .

[11]  R. Schröder,et al.  Cerebrovascular involvement in systemic AA and AL amyloidosis: a clear haematogenic pattern , 1999, Virchows Archiv.

[12]  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.

[13]  W. Banks,et al.  The putative blood-brain barrier transporter for the beta-amyloid binding protein apolipoprotein j is saturated at physiological concentrations. , 1997, Life sciences.

[14]  J. Vonsattel,et al.  Cerebral amyloid angiopathy without and with cerebral hemorrhages: A comparative histological study , 1991, Annals of neurology.

[15]  B. Ghetti,et al.  Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Weller.  Pathology of Cerebrospinal Fluid and Interstitial Fluid of the CNS: Significance for Alzheimer Disease, Prion Disorders and Multiple Sclerosis , 1998, Journal of neuropathology and experimental neurology.

[17]  P. Fraser,et al.  An important role of heparan sulfate proteoglycan (perlecan) in a model system for the deposition and persistence of fibrillar aβ-amyloid in rat brain , 1994, Neuron.

[18]  S. Younkin,et al.  Amyloid β protein levels in cerebrospinal fluid are elevated in early‐onset Alzheimer's disease , 1994 .

[19]  J. Growdon,et al.  Cerebrospinal fluid levels of amyloid β‐protein in alzheimer's disease: Inverse correlation with severity of dementia and effect of apolipoprotein e genotype , 1995, Annals of neurology.

[20]  L. Mucke,et al.  Increased central nervous system production of extracellular matrix components and development of hydrocephalus in transgenic mice overexpressing transforming growth factor-beta 1. , 1995, The American journal of pathology.

[21]  D. Selkoe,et al.  Permeability and Residual Plasma Volume of Human, Dutch Variant, and Rat Amyloid β-Protein 1-40 at the Blood–Brain Barrier , 1997, Neurobiology of Disease.

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

[23]  S. Younkin,et al.  Accumulation of beta-amyloid fibrils in pancreas of transgenic mice. , 1996, Neurobiology of aging.

[24]  B. Greenberg,et al.  An interaction between basement membrane and Alzheimer amyloid precursor proteins suggests a role in the pathogenesis of Alzheimer's disease. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[25]  M. Verbeek,et al.  Distribution of A beta-associated proteins in cerebrovascular amyloid of Alzheimer's disease. , 1998, Acta Neuropathologica.

[26]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[27]  T. Miyatake,et al.  Cerebral amyloid angiopathy: A significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly , 1993, Journal of Neurological Sciences.

[28]  D. Selkoe,et al.  Beta amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease. An immunoelectron microscopic study. , 1992, The American journal of pathology.

[29]  I. Lieberburg,et al.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. , 1990, Science.

[30]  B. Zlokovic,et al.  Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. , 1998, The Journal of clinical investigation.

[31]  R N Kalaria,et al.  Cerebral vessels in ageing and Alzheimer's disease. , 1996, Pharmacology & therapeutics.

[32]  P. Mantyh,et al.  Intra-arterial infusion of [125I]A beta 1-40 labels amyloid deposits in the aged primate brain in vivo. , 1996, Neuroreport.

[33]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[34]  M. Verbeek,et al.  Differences between the pathogenesis of senile plaques and congophilic angiopathy in Alzheimer disease. , 1997, Journal of Neuropathology and Experimental Neurology.

[35]  R. Motter,et al.  Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease , 1997 .

[36]  D. Premkumar,et al.  Production and increased detection of amyloid beta protein and amyloidogenic fragments in brain microvessels, meningeal vessels and choroid plexus in Alzheimer's disease. , 1996, Brain research. Molecular brain research.

[37]  S. Younkin,et al.  Accumulation of β-Amyloid fibrils in pancreas of transgenic mice , 1996, Neurobiology of Aging.

[38]  J. Wegiel,et al.  High levels of circulating β-amyloid peptide do not cause cerebral β-amyloidosis in transgenic mice , 1996 .

[39]  G. Schellenberg,et al.  Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease , 1996, Nature Medicine.

[40]  G. Glenner,et al.  Differences Between Vascular and Plaque Core Amyloid in Alzheimer's Disease , 1988, Journal of neurochemistry.

[41]  R. Roos,et al.  Amyloid β precursor protein-mRNA is expressed throughout cerebral vessel walls , 1999, Brain Research.

[42]  J. Palo,et al.  Amyloid in familial amyloidosis, Finnish type, is antigenically and structurally related to gelsolin. , 1990, The American journal of pathology.

[43]  R. Nicoll,et al.  Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  J. Bading,et al.  Cerebrovascular Accumulation and Increased Blood‐Brain Barrier Permeability to Circulating Alzheimer's Amyloid β Peptide in Aged Squirrel Monkey with Cerebral Amyloid Angiopathy , 1998, Journal of neurochemistry.

[45]  R. Petersen,et al.  Transthyretin amyloidosis: A new mutation associated with dementia , 1997, Annals of neurology.

[46]  W. V. Van Nostrand,et al.  Pathologic Amyloid β‐Protein Cell Surface Fibril Assembly on Cultured Human Cerebrovascular Smooth Muscle Cells , 1998 .

[47]  Hans Förstl,et al.  Analysis of Heterogeneous βA4 Peptides in Human Cerebrospinal Fluid and Blood by a Newly Developed Sensitive Western Blot Assay* , 1996, The Journal of Biological Chemistry.

[48]  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.

[49]  D. Selkoe,et al.  Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids , 1992, Nature.

[50]  D. Selkoe,et al.  Normal and abnormal biology of the beta-amyloid precursor protein. , 1994, Annual review of neuroscience.

[51]  M. Verbeek,et al.  Rapid Degeneration of Cultured Human Brain Pericytes by Amyloid β Protein , 1997 .

[52]  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. , 1990, Science.

[53]  M J Ball,et al.  beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[54]  C. Cotman,et al.  Amyloid β‐Protein Induces Its Own Production in Cultured Degenerating Cerebrovascular Smooth Muscle Cells , 1995 .

[55]  L. Walker,et al.  Cerebrovascular amyloidosis: experimental analysis in vitro and in vivo. , 1999, Histology and histopathology.

[56]  H. Budka,et al.  Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD 18G) , 1996, The American journal of pathology.

[57]  G. Perry,et al.  Degeneration of vascular muscle cells in cerebral amyloid angiopathy of Alzheimer disease , 1993, Brain Research.

[58]  H. Wiśniewski,et al.  Vascular β-amyloid in Alzheimer's disease angiopathy is produced by proliferating and degenerating smooth muscle cells , 1994 .

[59]  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.

[60]  L. Mucke,et al.  Levels and Alternative Splicing of Amyloid β Protein Precursor (APP) Transcripts in Brains of APP Transgenic Mice and Humans with Alzheimer's Disease (*) , 1995, The Journal of Biological Chemistry.

[61]  M. Emmerling,et al.  High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer's disease. , 1999, Biochemical and biophysical research communications.

[62]  L. Mucke,et al.  Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease , 1997, Nature.

[63]  Y. Ihara,et al.  Amyloid β‐proteins 1—40 and 1—42(43) in the soluble fraction of extra‐ and intracranial blood vessels , 1995 .

[64]  Agueda Rostagno,et al.  A stop-codon mutation in the BRI gene associated with familial British dementia , 1999, Nature.