Cerebral Amyloid Angiopathy

Weller, Roy O.; Massey, Adrian; Newman, Tracey; Hutchings, Margaret; Kuo, Yu Min; Roher, Alex E.

doi:10.1016/s0002-9440(10)65616-7

Cited by 444 publications

(119 citation statements)

References 41 publications

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“…However, our observation that CNS cells in or around the vessel wall produce copious amounts of apoE raises the possibility that apoE4 generated in this location might retain more A␤ than apoE3, leading to more severe CAA in apoE4 carriers. In line with this hypothesis, CAA in AD brains occurs along the perivascular spaces of small blood vessels and between smooth muscle cells in large vessels (Weller et al, 1998). Interestingly, apoE was not expressed along veins in the CNS of the EGFP apoE mice, and CAA is seldom found along the veins in AD brains (Weller et al, 1998).…”

Section: Discussionmentioning

confidence: 78%

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Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

Xu¹,

Bernardo²,

Walker³

et al. 2006

J. Neurosci.

414

333

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To study the profile and regulation of apolipoprotein E (apoE) expression in the CNS, we generated mice in which apoE expression can be detected in vivo with unprecedented sensitivity and resolution. cDNA encoding enhanced green fluorescent protein (EGFP) with a stop codon was inserted by gene targeting into the apoE gene locus (EGFP apoE ) immediately after the translation initiation site. Insertion of EGFP into one apoE allele provides a real-time location marker of apoE expression in vivo; the remaining allele is sufficient to maintain normal cellular physiology. In heterozygous EGFP apoE mice, EGFP was highly expressed in hepatocytes and peritoneal macrophages. EGFP was also expressed in brain astrocytes; however some astrocytes (ϳ25%) expressed no EGFP, suggesting that a subset of these cells does not express apoE. EGFP was expressed in Ͻ10% of microglia after kainic acid treatment, suggesting that microglia are not a major source of brain apoE. Although hippocampal neurons did not express EGFP under normal conditions, kainic acid treatment induced intense expression of EGFP in injured neurons, demonstrating apoE expression in neurons in response to excitotoxic injury. The neuronal expression was confirmed by in situ hybridization of mouse apoE mRNA and by anti-apoE immunostaining. Smooth muscle cells of large blood vessels and cells surrounding small vessels in the CNS also strongly expressed EGFP, as did cells in the choroid plexus. EGFP apoE reporter mice will be useful for studying the regulation of apoE expression in the CNS and might provide insights into the diverse mechanisms of apoE4-related neurodegeneration.

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Section: Discussionmentioning

confidence: 78%

“…In line with this hypothesis, CAA in AD brains occurs along the perivascular spaces of small blood vessels and between smooth muscle cells in large vessels (Weller et al, 1998). Interestingly, apoE was not expressed along veins in the CNS of the EGFP apoE mice, and CAA is seldom found along the veins in AD brains (Weller et al, 1998).…”

Section: Discussionmentioning

confidence: 78%

Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

Xu¹,

Bernardo²,

Walker³

et al. 2006

J. Neurosci.

414

333

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“…During this process vessels larger than 500 m in diameter were dissected and eliminated since in our experience they do not contain detectable thioflavine S staining cerebrovascular amyloid deposits (11). The washed leptomeningeal vessels were finely minced and submitted to 90% GDFA extraction and disruption in a glass homogenizer, which was followed by sieving through a nylon mesh (37 m).…”

Section: Methodsmentioning

confidence: 99%

The Human Amyloid-β Precursor Protein770 Mutation V717F Generates Peptides Longer Than Amyloid-β-(40-42) and Flocculent Amyloid Aggregates

Roher

Kokjohn

Esh

et al. 2004

Journal of Biological Chemistry

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One of the familial forms of Alzheimer's disease (AD) encodes the amyloid-␤ precursor protein (A␤PP) substitution mutation V717F. This mutation is relevant to AD research, since it has been utilized to generate transgenic mice models to study AD pathology and therapeutic interventions. Amyloid beta (A␤) peptides were obtained from the cerebral tissue of three familial AD subjects carrying the A␤PP V717F mutation. A combination of ultracentrifugation, size-exclusion, and reversephase high performance liquid chromatography, tryptic and cyanogen bromide hydrolysis, amino acid analysis, and matrix-assisted laser desorption ionization and surface-enhanced laser desorption ionization mass spectrometry was used to characterize the familial AD mutant A␤ peptides. The A␤PP V717F mutation, located 4 -6 residues beyond the wild-type A␤PP ␥-secretase cleavage site, yielded longer A␤ peptides with C termini between residues 43 and 54. In the cerebral cortex these peptides aggregated into thin water-and SDS-insoluble amyloid bundles that condensed into flocculent spherical plaques. In the leptomeningeal arteries the amyloid was deposited in moderate amounts and was primarily composed of the shorter and more soluble A␤ species ending at residues 40, 42, and 44. The single V717F mutation in A␤PP results in distinctive and drastic changes in the length and tertiary structure of A␤ peptides, which appear to be responsible for the earlier clinical manifestations of dementia and death of these patients. Alzheimer's disease (AD)1 is characterized by profuse amyloid fibril deposition in cortical neuritic plaques and cerebral vessel walls (1). The amyloid-␤ (A␤) peptides consist predominately of 40 -42 amino acid residues derived from amyloid-␤ precursor protein (A␤PP) proteolysis. Rare, familial mutations both within the A␤ coding domain and flanking N-and Cterminal regions have been described that result in A␤ deposition, dementia, and in some cases hemorrhagic stroke (2, 3). In addition, mutations in the presenilin 1 and 2 genes also produce the characteristic neuropathological lesions and clinical expression of AD dementia (3, 4). Despite the fact that familial AD (FAD) patients reproduce many of the same characteristic features prominent in sporadic AD, the vast majority of dementia cases do not possess any obvious genetic basis.One of the best characterized forms of FAD is the Val 3 Phe mutation at position 717 of the A␤PP (A␤PP 770 isoform numbering), a rare mutation expressed in a single family (5). Neurological disease is clinically manifested in relatively young individuals who become demented in their late thirties to early forties and die at about fifty years of age (6, 7). This mutation is of great biological importance since it has been utilized to construct an A␤PP transgenic (Tg) mouse in combination with the platelet-derived growth factor promoter to enhance A␤ production and amyloid deposition (8, 9). Known as the PDAPP Tg mouse, the model is widely employed in academic and industrial settings to study fundamental A␤...

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“…5 and Table 1). The development of amyloid fibrils is concentration-dependent in vitro (24), and, for plaques and CAA to form in regions with low levels of expression, APP or A␤ must either be transported to that location (25) or must circulate through another mechanism: for instance, CSF (17), brain interstitial fluid (ISF) (26), or blood (27).…”

Section: Transport or Circulation Of App͞a␤ Play A Role In Cerebral Amentioning

confidence: 99%

Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid

Calhoun

Burgermeister

Phinney

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

381

264

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Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer's disease pathology, namely the extracellular deposition of amyloid plaques. Here, we describe significant deposition of amyloid ␤ (A␤) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to that observed in human aging and Alzheimer's disease. Amyloid deposition occurred preferentially in arterioles and capillaries and within individual vessels showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was associated with local neuron loss, synaptic abnormalities, microglial activation, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of A␤ in cerebrospinal fluid, and regional localization of CAA in APP23 mice suggest transport and drainage pathways rather than local production or blood uptake of A␤ as a primary mechanism underlying cerebrovascular amyloid formation. APP23 mice on an App-null background developed a similar degree of both plaques and CAA, providing further evidence that a neuronal source of APP͞A␤ is sufficient to induce cerebrovascular amyloid and associated neurodegeneration.

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Cerebral Amyloid Angiopathy

Cited by 444 publications

References 41 publications

Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

The Human Amyloid-β Precursor Protein770 Mutation V717F Generates Peptides Longer Than Amyloid-β-(40-42) and Flocculent Amyloid Aggregates

Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid

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