Human apolipoprotein E4 accelerates β‐amyloid deposition in APPsw transgenic mouse brain

Carter, Donald B.; Dunn, Edwige; McKinley, Denise D.; Stratman, Nancy C.; Boyle, Timothy P.; Kuiper, Susan L.; Oostveen, Jo A.; Weaver, Royal J.; Boller, Jennifer A.; Gurney, Mark E.

doi:10.1002/ana.1134

Cited by 67 publications

(42 citation statements)

References 30 publications

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“…The findings that apoE4 stimulates deposition of A␤ and apoE deficiency blocks formation of fibrillar A␤ deposits are in accordance with and extend previous studies with APP ϫ apoE doubletransgenic mice and with APP-transgenic mice on a null apoE mouse background (24,36,39,42,43). Formation of A␤ deposits did not require apoE, but it was accelerated significantly and in an isoform-specific fashion by apoE4 (Figs.…”

Section: Discussionsupporting

confidence: 92%

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

Dolev

Michaelson

2004

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

102

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The amyloid-␤ (A␤) peptide, a major pathological hallmark of Alzheimer's disease (AD), undergoes a cascade of interactions resulting in the formation of soluble aggregates and their conversion in the brain to insoluble deposits and mature senile plaques. Furthermore, the apoE4 isoform of apolipoprotein E (apoE), which is the major genetic risk factor of AD, is associated with increased A␤ deposition. It is not known how the different A␤ aggregates in the amyloid cascade are formed, contribute to the pathogenesis of AD, or are affected by apoE4. To investigate the initial aggregation stages underlying the amyloid cascade in vivo and how apoE affects them, we examined the effects of prolonged inhibition and subsequent reactivation of the A␤-degrading protease neprilysin on deposition, disaggregation, and fibrillization of A␤ in apoEtransgenic and control mice. In control mice, intracerebroventricular infusion of thiorphan, which inhibits neprilysin, induced A␤42 and A␤40 deposition and fibrillization. On termination of thiorphan treatment, the number of A␤ deposits decreased, whereas the fibrillar A␤ deposits were unaffected. Similar treatments in apoE-deficient mice and mice transgenic for human apoE4 or apoE3 revealed that apoE4 enhances specifically the nucleation and aggregation of immunopositive A␤ deposits and that reversible disaggregation of these deposits and their irreversible conversion to fibrillar deposits are stimulated similarly by the different apoE isoforms. Deposition of A␤ and its enhancement by apoE4 were accompanied by increased astrogliosis both far from and near the A␤ deposits, suggesting that astrogliosis might be triggered by both insoluble and soluble A␤ aggregates.C onverging genetic and histopathological observations led to the formulation of the amyloid hypothesis, which proposes that accumulation of amyloid-␤ (A␤) peptide, a major constituent of the brain plaques characteristic of Alzheimer's disease (AD), is the primary event in AD pathogenesis (1, 2). Recent findings suggest that brains of individuals with AD also contain soluble and neurotoxic A␤ oligomers, which seem to be an intermediate state in the A␤-aggregation cascade, whose downstream product is the senile plaque (3-10). There is poor correlation between the severity of dementia and the density of amyloid plaques in AD (11-13); furthermore, in mice transgenic for the human A␤ precursor protein (APP), synaptic degeneration and cognitive decline are observed even before amyloid is deposited (14-16). This finding suggests that the pathological effects of A␤ in AD are mediated by A␤ aggregates that precede the formation of the senile plaque. The relative contributions of the different soluble and insoluble A␤ aggregates to the pathology of AD and the mechanisms underlying their formation in vivo are not yet known.Apolipoprotein E (apoE), the major brain lipid-binding protein, is expressed in humans as three isoforms (apoE2, apoE3, and apoE4), which differ in one or two amino acids (17). The apoE4 genotype is the major genetic ...

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Section: Discussionsupporting

confidence: 92%

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

Dolev

Michaelson

2004

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

102

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“…Our data are in line with a study demonstrating promotion of parenchymal and vascular amyloid by human ApoE4, without affecting the metabolism of APP. 19 We conclude that any modulation of the amyloid pathology by ApoE4 must be ascribed to postsynthetic events, taking place after the amyloid peptides are excised from APP as a consequence of intra-or extracellular interaction with ApoE4 lipoproteins that slow down clearance and degradation of A␤. Moreover, we demonstrate that the cellular origin of ApoE4 plays an important role in determining the fate of the amyloid peptides.…”

Section: Cellular Mechanisms Involved In Neuronal Versus Glial Apoe4mentioning

confidence: 85%

“…13,16,17 Another study demonstrated, however, that expression of human ApoE4 but not of ApoE3, both under control of the transferrin gene promoter, accelerated deposition of amyloid in APP/Swe transgenic mice. 19 In a similar study, overexpression of either ApoE isoform under control of the prion gene promoter neither accelerated nor increased the amyloid burden, nor markedly affected the metabolism before amyloid deposition even in the presence of mutant presenilin-1 in tripletransgenic mice. 20 In addition to parenchymal amyloid plaques, the vascular deposits presenting as cerebral congophilic amyloid angiopathy (CAA) are a major pathological sign in AD 21 with a prevalence of more than 90% in the oldest patients.…”

mentioning

confidence: 89%

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

Dooren

Muyllaert

Borghgraef

et al. 2006

The American Journal of Pathology

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Apolipoprotein E4 (ApoE4) is associated with Alzheimer's disease by unknown mechanisms. We generated six transgenic mice strains expressing human ApoE4 in combination with mutant amyloid precursor protein (APP) and mutant presenilin-1 (PS1) in single-, double-, or triple-transgenic combinations. Diffuse, but not dense, amyloid plaque-load in subiculum and cortex was increased by neuronal but not glial ApoE4 in old (15 months) double-transgenic mice, whereas both diffuse and dense plaques formed in thalamus in both genotypes. Neuronal and glial ApoE4 promoted cerebral amyloid angiopathy as extensively as mutant PS1 but with pronounced regional differences: cortical angiopathy was induced by neuronal ApoE4 while thalamic angiopathy was again independent of ApoE4 source. Angiopathy correlated more strongly with soluble A␤40 and A␤42 levels in cortex than in thalamus throughout the six genotypes. Neither neuronal nor glial ApoE4 affected APP proteolytic processing, as opposed to mutant PS1. Neuronal ApoE4 increased soluble amyloid levels more than glial ApoE4, but the A␤42/40 ratios were similar, although significantly higher than in single APP transgenic mice. We conclude that although the cellular origin of ApoE4 differentially affects regional amyloid pathology, ApoE4 acts on the disposition of amyloid peptides downstream from their excision from APP but without induction of tauopathy. Alzheimer's disease (AD) is characterized by pathological accumulations in the brain of extracellular amyloid plaques and intraneuronal accumulations of protein tau known as neurofibrillary tangles. The amyloid peptides A␤40 and A␤42 are the major components of the amyloid deposits in parenchyma and vasculature.1 The amyloid peptides are excised from the integral membrane protein amyloid precursor protein (APP) by sequential endoproteolytic cleavages by ␤-and ␥-secretases.2 The exact causes and consequences, in terms of normal processes and mechanisms that are disturbed by the amyloid peptides and causing neurodegeneration, remain primarily unclear. 3Besides APP and presenilins (PS1, PS2), the apolipoprotein E (ApoE) is genetically linked to AD. 4 The ApoE4 lipoprotein or its encoding ⑀4 allele, are epidemiologically associated with AD and confer an increased risk and earlier age of onset relative to the more common ApoE3 protein or ⑀3 allele. [5][6][7] ApoE is a 34-kd protein abundantly expressed in liver and brain. In the circulation, ApoE-lipoproteins mediate transport of lipids and cholesterol from and to liver and extrahepatic tissues. In contrast to the peripheral functions of ApoE that are well understood, details of its actions in the central nervous system remain primarily unknown. Actually, the epidemiological association of the ⑀4-allele to AD provided a strong impetus to research, by pointing out our lack of understanding the physiology of lipid and cholesterol homeostasis and of their transport in brain, in particular the contribution of ApoE and various ApoE receptors. 8,9

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“…Given that the stimulus for amyloid processing and deposition is different between these two experimental systems, a direct comparison is not possible. Non-transgenic BALB/c mice typically do not develop amyloid pathology [8,10], however following experimental induction, these mice developed deposits consisting solely of mouse amyloid. Mouse A␤ is highly homologous to human A␤ [15,20], but typically does not deposit into plaques.…”

Section: Experimental Models Of Admentioning

confidence: 99%

Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice

Little

Hammond

MacIntyre

et al. 2004

Neurobiology of Aging

206

197

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Amyloid deposits resembling plaques found in Alzheimer's disease (AD) brains were formed in the brains of non-transgenic BALB/c mice following intranasal infection with Chlamydia pneumoniae. The mice were infected at 3 months of age with C. pneumoniae isolated from an AD brain. Infection was confirmed by light and electron microscopy in olfactory tissues of the mice. C. pneumoniae was still evident in these tissues 3 months after the initial infection indicating that a persistent infection had been established. Amyloid beta (A␤) 1-42 immunoreactive deposits were identified in the brains of infected BALB/c mice up to 3 months post-infection with the density, size, and number of deposits increasing as the infection progressed. A subset of deposits exhibited thioflavin-s labeling. Intracellular A␤1-42 labeling was observed in neuronal cells. Experimental induction of amyloid deposition in brains of non-transgenic BALB/c mice following infection with C. pneumoniae may be a useful model for furthering our understanding of mechanisms, linked to infection, involved in the initiation of the pathogenesis of sporadic AD.

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Human apolipoprotein E4 accelerates β‐amyloid deposition in APPsw transgenic mouse brain

Cited by 67 publications

References 30 publications

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

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

Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice

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