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

Xu, Feng; Vitek, Michael P.; Colton, Carol A.; Previti, Mary Lou; Gharkholonarehe, Nastaran; Davis, James Earl; Nostrand, William E. Van

doi:10.1523/jneurosci.1042-08.2008

Cited by 23 publications

(17 citation statements)

References 38 publications

(47 reference statements)

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“…The higher levels of CAA in APOE-ε2 and APOE-ε4 brains suggest that both apoE4 and apoE2 may cause deficits in the clearance of Ab. In mice expressing Dutch and Iowa mutant Ab, the expression of any of the 3 human apoE isoforms had similar effects: reduced Ab in the microvasculature and increased parenchymal Ab (40, 41). Human apoE seems to have less ability to clear Ab from the brain compared to mouse Ab (42), and in these models, Ab clearance may be so impaired that it is not even moved from the parenchyma to the vasculature.…”

Section: Discussionmentioning

confidence: 96%

APOE-ε2 and APOE-ε4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature

Nelson

Pious

Jicha

et al. 2013

J Neuropathol Exp Neurol

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The APOE ε4 allele correlates with increased risk of Alzheimer disease (AD) and increased parenchymal amyloid plaques. We tested how the APOE genotype correlated with cerebral amyloid angiopathy (CAA) by analyzing 371 brains for parenchymal and meningeal CAA in 4 brain regions (frontal, parietal, temporal, and occipital neocortex). The overall severity of CAA was highest in the occipital lobe. APOE-ε4/4 brains (n = 22) had the highest levels of CAA across regions. In the occipital lobe, nearly all APOE-ε4/4 cases were scored with the highest level of CAA (meninges, 95% of cases; parenchyma, 81%). In this brain region as in others, APOE-ε3/4 brains (n = 115) showed consistently less CAA that APOE-ε4/4 brains (meninges, 43%; parenchyma, 43%). APOE-ε3/3 brains (n = 182) showed even less CAA (meninges, 19%; parenchyma, 19%). Interestingly, APOE-ε2/3 cases (n = 42) had more CAA than APOE-ε3/3 (meninges, 44%; parenchyma, 32%), despite a reduced risk for AD in the APOE-ε2/3 individuals. APOE-ε4/4 brains also had the fewest regions without CAA, whereas APOE-ε3/3 brains had the most. Ordinal regression analyses demonstrated significant impacts of APOE-ε2 and APOE-ε4 on CAA in at least some brain region. These data demonstrate that APOE genotype correlations with Ab deposition in CAA only incompletely correspond to other AD-linked brain pathologies.

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Section: Discussionmentioning

confidence: 96%

APOE-ε2 and APOE-ε4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature

Nelson

Pious

Jicha

et al. 2013

J Neuropathol Exp Neurol

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“…Existing data show that the deposition of amyloid is seen as linearly distributed in the capillary BL [65], in the pathology defined as CAA, frequently present in AD, and much less common in cerebral and leptomeningeal arteries [60]. It has been demonstrated that human ApoE influences cerebral amyloid accumulation in transgenic mice primarily in the form of fibrillar cerebral microvascular amyloid [66]. An interesting aspect recently debated in clinical neuropathology is that the fibrillar amyloid is also found in brains of many cognitively normal aged individuals and it is still not known whether this reflects a predisposition to AD [67].…”

Section: Structural Changes On the Cortical Capillariesmentioning

confidence: 99%

A Hyperlipidemic Diet Induces Structural Changes in Cerebral Blood Vessels

Constantinescu¹,

Safciuc²,

Sima³

2011

CNR

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The cerebrovascular pathology is an important contributor to the death rate presently. Hyperlipidemia , an established risk factor for cardiovascular diseases, is also incriminated in the neurodegenerative disorders. The aim of this study was to evaluate the effect of a hyperlipidemic (HL) diet on the morphology of the cerebral vessels and on the amyloid deposition in the HL hamster, an accepted model of atherosclerosis. Hamsters fed a HL diet were tested periodically for serum parameters and sacrificed after 3 and 6 months. The methods used were: paraffin embedding, thioflavin S amyloid staining, fluorescence and electron microscopy (EM). Increased serum cholesterol and triglycerides characterized the HL hamsters. The carotid arteries developed fatty streaks after 3 months and atherosclerotic plaques after 6 months HL diet. The brain cortex comprised irregularly shaped microvessels with large perivascular spaces, enlarged endothelial cells (EC) and occasionally a lumen full of lipoprotein particles. The thioflavin S reaction revealed a discreet staining of the capillaries walls; the EC cytoplasm and basal lamina contained a fibrillar material, with a pattern similar to an incipient amyloid deposit. Some large meningeal vessels from animals with serum cholesterol over 1000 mg/dl presented an intense autofluorescence in the adventitia; EM examination identified lipid-loaded perivascular cells in these areas. In conclusion, the detected morphological changes induced by the HL diet could represent a serious impairment for the normal brain function. These data may contribute to the better understanding of the risks of hyperlipidemia for the mental health, and its reversal could become a new therapeutic approach for neurodegenerative disorders.

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“…apoE4 also promotes the formation of cerebral amyloid angiopathy (CAA) in a mouse model of AD (30). Human apoE3 and apoE4 can both substantially increase parenchymal deposition of fibrillar Aβ in a mouse model of familial Dutch and Iowa CAA (31).…”

Section: Introductionmentioning

confidence: 99%

apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain

Deane¹,

Sagare²,

Hamm³

et al. 2008

J. Clin. Invest.

656

596

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Neurotoxic amyloid β peptide (Aβ) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence Aβ accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts Aβ clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). Aβ binding to apoE4 redirected the rapid clearance of free Aβ40/42 from the LDL receptor-related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and Aβ-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as Aβ-apoE2 and Aβ-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than Aβ-apoE4 complexes. Astrocytesecreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with Aβ were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2-to 3-fold slower rates. Thus, apoE isoforms differentially regulate Aβ clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.

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

Cited by 23 publications

References 38 publications

APOE-ε2 and APOE-ε4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature

APOE-ε2 and APOE-ε4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature

A Hyperlipidemic Diet Induces Structural Changes in Cerebral Blood Vessels

apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain

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