Reducing Cerebral Microvascular Amyloid-β Protein Deposition Diminishes Regional Neuroinflammation in Vasculotropic Mutant Amyloid Precursor Protein Transgenic Mice

Miao, Jianting; Vitek, Michael P.; Xu, Feng; Previti, Mary Lou; Davis, James Earl; Nostrand, William E. Van

doi:10.1523/jneurosci.1306-05.2005

Cited by 61 publications

(56 citation statements)

References 42 publications

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“…For example, previous work in human A␤PP transgenic mice showed that the absence of endogenous mouse ApoE strongly reduced the deposition of normal human A␤ in the CNS (Bales et al, 1999;Holtzman, 2001Holtzman, , 2004Fryer et al, 2003). Similarly, we found that the lack of endogenous mouse ApoE prevented Dutch/Iowa CAA mutant cerebral microvascular amyloid accumulation and primarily reduced parenchymal diffuse A␤ deposits in Tg-SwDI mice (Miao et al, 2005b). Furthermore, in this study, we showed that the strong reduction of fibrillar cerebral microvascular A␤ deposition in Tg-SwDI mice decreases microvascular amyloid-induced neuroinflammation.…”

Section: Discussionsupporting

confidence: 80%

“…The finding that Tg-SwDI mice accumulate extensive cerebral microvascular A␤, despite low levels of transgene-directed human A␤PP expression, appears to primarily result from ineffective clearance of Dutch/Iowa mutant A␤ from brain across the blood-brain barrier into the circulation (Davis et al, , 2006Deane et al, 2004). In Tg-SwDI mice, cerebral microvascular amyloid deposition is intimately linked with a robust neuroinflammatory response, highlighted by localized strong microglial activation and deficits in spatial learning and memory (Miao et al, 2005b;Fan et al, 2007;Xu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

Vitek²,

Colton³

et al. 2008

J. Neurosci.

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Human apolipoprotein (ApoE) genotype influences the development of Alzheimer's disease and cerebral amyloid angiopathy (CAA). Specific mutations within the amyloid-␤ protein (A␤) peptide have been identified that cause familial forms of CAA. However, the effect of APOE genotype on accumulation of CAA mutant A␤ in brain is not well understood. In the present study, we determined how human ApoE3 or ApoE4 influence cerebral A␤ accumulation in transgenic mice (Tg-SwDI) that accumulate human Dutch/Iowa (E22Q/D23N) CAA mutant A␤ in brain, primarily in the form of fibrillar cerebral microvascular amyloid. Using Tg-SwDI mice bred onto a human APOE3/3 or human APOE4/4 background, we found that both human ApoE3 and ApoE4 proteins led to a strong reduction in the amount of cerebral microvascular amyloid with an unexpected concomitant appearance of extensive fibrillar parenchymal plaque amyloid. There was strong colocalization of all ApoE proteins with fibrillar amyloid deposits in the mice. In Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice, there was no change in the levels of total A␤ 40 and A␤ 42 or in the amounts of soluble and insoluble A␤ in brain compared with Tg-SwDI mice on the endogenous mouse APOE background. The shift from primarily cerebral microvascular amyloid to parenchymal plaque amyloid in Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice resulted in a parallel shift in the association of activated microglia. These findings indicate that human ApoE has a strong influence on the spatial development of human Dutch/Iowa CAA mutant amyloid accumulation in mouse brain and that microglial activation is in response to the spatial accumulation of fibrillar amyloid.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

Vitek²,

Colton³

et al. 2008

J. Neurosci.

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“…5A). To compare APPsw͞NOS2 Ϫ/Ϫ with APPsw littermates, we directly measured soluble and insoluble A␤40 and A␤42 levels in brain lysates by using a quantitative ELISA (19,20). Total brain A␤ levels were significantly greater in APPsw͞NOS2 Ϫ/Ϫ mice compared with APPsw littermate controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Soluble and insoluble pools of A␤40 and A␤42 were measured with a specific ELISA and differential brain extractions as described (19,20).…”

Section: Methodsmentioning

confidence: 99%

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

Colton¹,

Vitek²,

Wink

et al. 2006

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

123

103

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“…Derived from the amyloid protein precursor, Aβ aggregates in plaques in the brain and in cerebral vessels are a diagnostic feature of AD [37]. Aβ deposited in plaques in the walls of cerebral blood vessels causes cerebral amyloid angiopathy (CAA) [100], and is available to bind to circulating cells including erythrocytes [65,71,76]. Amyloid deposits in cerebral vessels can obliterate the lumens of cerebral arteries and damage the endothelium and basal lamina, causing a breakdown of the blood brain barrier (BBB), ischemia, and neurodegeneration [51,71,102].…”

Section: Aβ and Cerebral Amyloid Angiopathymentioning

confidence: 99%

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Perry

Gearhart

Wiener

et al. 2008

Neurobiology of Aging

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From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to Aβ1-42. We showed the oxidized form 1 These authors are co-corresponding authors for all stages of refereeing and publication and contributed equally to this work. Rodney T. Perry; Rm. 210H, 1665 University Blvd.; University of Alabama at Birmingham, Birmingham, USA; Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure Statement:I so state for myself and on behalf of the other authors on the manuscript, Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease, that we have no conflicts and sources of funding that influence the results of this paper, the data is not published or submitted elsewhere, and that appropriate approval and procedures were used concerning human subjects. I also verify that all authors on this manuscript have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of adult Hb (metHb A) binds with greater affinity to Aβ1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C→T) at −158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with Aβ and may protect against the development of AD.

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Reducing Cerebral Microvascular Amyloid-β Protein Deposition Diminishes Regional Neuroinflammation in Vasculotropic Mutant Amyloid Precursor Protein Transgenic Mice

Cited by 61 publications

References 42 publications

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

NO synthase 2 ( NOS2 ) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

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