Cerebral vascular accumulation of Dutch‐type Aβ42, but not wild‐type Aβ42, in hereditary cerebral hemorrhage with amyloidosis, Dutch type

Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA‐D), is an autosomal dominant disorder caused by the Dutch mutation (E693Q) in the β‐amyloid precursor protein. This mutation produces an aberrant amyloid β (Aβ) species (AβE22Q) and causes severe meningocortical vascular Aβ deposition. We analyzed the Aβ composition of the vascular amyloid in the brains of HCHWA‐D patients. Immunohistochemistry demonstrated that the vascular amyloid contained both Aβ40 and Aβ42, with a high Aβ40/Aβ42 ratio. In Western blotting of cerebral microvessel fractions isolated from the brains, both wild‐type and Dutch‐type Aβ40 were observed as major species. Reverse‐phase HPLC‐mass spectrometric analysis of the fractions revealed both wild‐type and Dutch‐type Aβ38 as the other main components of the vascular amyloid. Moreover, we detected peaks corresponding to Dutch‐type Aβ42 but not to wild‐type Aβ42. These results suggest a pathogenic role for the mutant Aβ42 in addition to the mutant Aβ40 in the cerebral amyloid angiopathy of HCHWA‐D. © 2007 Wiley‐Liss, Inc.

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

[2]  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.

[3]  B. Zlokovic,et al.  Substitution at codon 22 reduces clearance of Alzheimer’s amyloid-β peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood , 2002, Neurobiology of Aging.

[4]  M. Staufenbiel,et al.  Electrophoretic Separation of βA4 Peptides (1–40) and (1–42) , 1996 .

[5]  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.

[6]  D. Mann,et al.  Deposition of beta-amyloid subtypes 40 and 42 differentiates dementia with Lewy bodies from Alzheimer disease. , 1999, Archives of neurology.

[7]  D. Selkoe,et al.  Mass spectrometry of purified amyloid beta protein in Alzheimer's disease. , 1992, The Journal of biological chemistry.

[8]  D. Selkoe,et al.  Identification of a stable fragment of the Alzheimer amyloid precursor containing the beta-protein in brain microvessels. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Westaway,et al.  Enhanced accumulation of tau in doubly transgenic mice expressing mutant βAPP and presenilin-1 , 2006, Brain Research.

[10]  D. Pollen,et al.  Amyloid-β-protein isoforms in brain of subjects with PS1-linked, βAPP-linked and sporadic Alzheimer disease , 1998 .

[11]  D. Craik,et al.  Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch-type hereditary cerebral haemorrhage with amyloidosis. , 1994, European journal of biochemistry.

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

[13]  B. Zlokovic.  Clearing amyloid through the blood–brain barrier , 2004, Journal of neurochemistry.

[14]  R. Roos,et al.  Hereditary cerebral hemorrhage with amyloidosis (Dutch): a model for congophilic plaque formation without neurofibrillary pathology , 2004, Acta Neuropathologica.

[15]  H. Mantsch,et al.  Comparative Analysis of Human and Dutch-Type Alzheimer β-Amyloid Peptides by Infrared Spectroscopy and Circular Dichroism , 1993 .

[16]  T. Wisniewski,et al.  Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. , 1991, Biochemical and biophysical research communications.

[17]  L. Lue,et al.  Insulin-degrading Enzyme in Brain Microvessels , 2004, Journal of Biological Chemistry.

[18]  Khadija Iqbal,et al.  Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer's disease. , 1993, Archives of biochemistry and biophysics.

[19]  C. Soto,et al.  The -Helical to -Strand Transition in the Amino-terminal Fragment of the Amyloid -Peptide Modulates Amyloid Formation * , 1995, The Journal of Biological Chemistry.

[20]  H. Vinters,et al.  Toxicity of Dutch (E22Q) and Flemish (A21G) mutant amyloid beta proteins to human cerebral microvessel and aortic smooth muscle cells. , 2000, Stroke.

[21]  D. Holtzman,et al.  Human Apolipoprotein E4 Alters the Amyloid-β 40:42 Ratio and Promotes the Formation of Cerebral Amyloid Angiopathy in an Amyloid Precursor Protein Transgenic Model , 2005, The Journal of Neuroscience.

[22]  I. Tesseur,et al.  Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APP in neurons , 2000, Neurobiology of Aging.

[23]  T. V. Van Dooren,et al.  Neuronal or glial expression of human apolipoprotein e4 affects parenchymal and vascular amyloid pathology differentially in different brain regions of double- and triple-transgenic mice. , 2006, The American journal of pathology.

[24]  S. Tsuji,et al.  Aβ1–40 but not Aβ1–42 levels in cortex correlate with apolipoprotein E ϵ4 allele dosage in sporadic Alzheimer's disease , 1997, Brain Research.

[25]  B. Winblad,et al.  Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. , 1996, The American journal of pathology.

[26]  S. V. van Duinen,et al.  Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Gearing,et al.  Aβ‐peptide length aid apolipoprotein E genotype in Alzheimer's disease , 1996 .

[28]  H. Yamaguchi,et al.  Age-related plaque morphology and C-terminal heterogeneity of amyloid β in Dutch-type hereditary cerebral hemorrhage with amyloidosis , 2000, Acta Neuropathologica.

[29]  R. Roos,et al.  Morphology of cerebral plaque-like lesions in hereditary cerebral hemorrhage with amyloidosis (Dutch) , 2004, Acta Neuropathologica.

[30]  W. V. Van Nostrand,et al.  Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  R. Roos,et al.  Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch type (HCHWA‐D): II ‐ A Review of Histopathological Aspects , 1996, Brain pathology.

[32]  D. Holtzman,et al.  The Bad Seed in Alzheimer’s Disease , 2005, Neuron.

[33]  R. Roos,et al.  Microvasculopathy is associated with the number of cerebrovascular lesions in hereditary cerebral hemorrhage with amyloidosis, Dutch type. , 1998, Stroke.

[34]  T. Saido,et al.  Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Aβ to physiologically relevant proteolytic degradation , 2003, The Lancet.

[35]  R. Roos,et al.  Ultrastructural evidence of early non-fibrillar Aβ42 in the capillary basement membrane of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type , 1999, Acta Neuropathologica.

[36]  A. Roses,et al.  Proteolytic processing of presenilin‐1 (PS‐1) is not associated with Alzheimer's disease with or without PS‐1 mutations , 1997, FEBS letters.

[37]  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.

[38]  J. Hardy,et al.  Aβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice , 2005, Neuron.

[39]  G. Glenner,et al.  Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. , 1984, Biochemical and biophysical research communications.

[40]  D. Walsh,et al.  Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer's amyloid β/A4 peptide , 1993, Neuroscience Letters.