β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Increases Amyloid Deposition in Brain Parenchyma but Reduces Cerebrovascular Amyloid Angiopathy in Aging BACE × APP[V717I] Double-Transgenic Mice

Willem, Michael; Dewachter, Ilse; Smyth, Neil; Dooren, Tom Van; Borghgraef, Peter; Haass, Christian; Leuven, Freddy Van

doi:10.1016/s0002-9440(10)63419-0

Cited by 53 publications

(55 citation statements)

References 45 publications

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“…These results are consistent with a recent study (19) but differ from results obtained in other hBACE1/hAPP models (20,21,40,41). Several factors might account for these differences, including the genetic background of the mice analyzed.…”

Section: Discussionsupporting

confidence: 89%

High β-Secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-β Levels

Rockenstein

Mante

Alford

et al. 2005

Journal of Biological Chemistry

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Amyloid-␤ peptides (A␤) are widely presumed to play a causal role in Alzheimer disease. Release of A␤ from the amyloid precursor protein (APP) requires proteolysis by the ␤-site APP-cleaving enzyme (BACE1). Although increased BACE1 activity in Alzheimer disease brains and human (h) BACE1 transgenic (tg) mice results in altered APP cleavage, the contribution of these molecular alterations to neurodegeneration is unclear. We therefore used the murine Thy1 promoter to express high levels of hBACE1, with or without hAPP, in neurons of tg mice. Compared with hAPP mice, hBACE1/hAPP doubly tg mice had increased levels of APP C-terminal fragments (C89, C83) and decreased levels of full-length APP and A␤. In contrast to non-tg controls and hAPP mice, hBACE1 mice and hBACE1/hAPP mice showed degeneration of neurons in the neocortex and hippocampus and degradation of myelin. Neurological deficits were also more severe in hBACE1 and hBACE1/ hAPP mice than in hAPP mice. These results demonstrate that high levels of BACE1 activity are sufficient to elicit neurodegeneration and neurological decline in vivo. This pathogenic pathway involves the accumulation of APP C-terminal fragments but does not depend on increased production of human A␤. Thus, inhibiting BACE1 may block not only A␤-dependent but also A␤-independent pathogenic mechanisms.The precise mechanisms leading to neurodegeneration in Alzheimer disease (AD) 2 are not completely understood. However, diverse lines of evidence suggest that alterations in the processing of the amyloid precursor protein (APP), leading to the accumulation of amyloid-␤ peptides (A␤), play a key role in the pathogenesis of AD (1-3). Various products are derived from APP through alternative proteolytic cleavage, and enormous progress has recently been made in identifying the enzymes involved (3-11).Cleavage of APP by ␣-secretase results in the secretion of a large N-terminal ectodomain. In an alternative pathway, ␤-secretase generates a shorter secreted N-terminal fragment and APP C-terminal fragments (CTFs) C89 and C99, which remain membrane-bound. The latter fragments are then further cleaved by ␥-secretase, resulting in the production of A␤ peptides. The ␤-site APP-cleaving enzyme (BACE1) accounts for most of the ␤-secretase activity in the brain (1,(5)(6)(7)9). BACE1 is a typical aspartic protease; cleavage of the prodomain to generate the mature enzyme occurs at the C-terminal site resulting in the generation of a mature protein starting at Glu-46 (12). Recent evidence suggests that the pathogenesis of AD involves alterations in the activity of BACE1. A polymorphism in the BACE1 gene has been reported to influence AD risk (13). Compared with nondemented controls, BACE1 immunoreactivity was increased around amyloid plaques in AD brains; levels of BACE1 were elevated in AD brain homogenates (14 -17) and correlated with the levels of APP CTFs and with A␤ 1-x and A␤ 1-42 (18). The potential pathogenic role of increased BACE activity has been investigated in vivo by analyzing the metabolism of A...

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Section: Discussionsupporting

confidence: 89%

High β-Secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-β Levels

Rockenstein

Mante

Alford

et al. 2005

Journal of Biological Chemistry

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“…Although the total BACE1 increase in AD is relatively small (ϳ1.6-fold), BACE1 concentrations in neurons near plaques appear high and may stimulate local A␤ production. In support of this hypothesis, modestly elevated BACE1 levels cause increased A␤ production in vivo in BACE1 transgenic mice (Bodendorf et al, 2002;Chiocco et al, 2004;Mohajeri et al, 2004;Willem et al, 2004;Chiocco and Lamb, 2005;Lee et al, 2005;Ozmen et al, 2005) and in APP transgenic mice treated with energy inhibitors (Velliquette et al, 2005). Because perforant pathway axons are a major source of A␤ for plaque formation in the outer molecular layer of the hippocampus (Lazarov et al, 2002;Sheng et al, 2002), we speculate that BACE1 and APP accumulation in dystrophic neurites around plaques could drive local A␤ overproduction.…”

Section: Role Of Bace1 Elevation In Admentioning

confidence: 66%

β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis

Zhao¹,

Fu²,

Yasvoina³

et al. 2007

J. Neurosci.

334

359

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␤-Site amyloid precursor protein cleaving enzyme 1 (BACE1) (␤-secretase) initiates generation of ␤-amyloid (A␤), which plays an early role in Alzheimer's disease (AD). BACE1 levels are increased in postmortem AD brain, suggesting BACE1 elevation promotes A␤ production and AD. Alternatively, the BACE1 increase may be an epiphenomenon of late-stage AD. To distinguish between these possibilities, we analyzed BACE1 elevation using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1Ϫ/Ϫ mice, which mount a robust anti-BACE1 immune response. Previous BACE1 immunohistochemical studies lack consistent results because typical BACE1 antibodies produce nonspecific background, but BACE-Cat1 immunolabels BACE1 only. BACE1 elevation was recapitulated in two amyloid precursor protein (APP) transgenic mouse lines. 5XFAD mice form amyloid plaques at young ages and exhibit neuron loss. In contrast, Tg2576 form plaques at a more advanced age and do not show cell death. These two mouse lines allow differentiation between early A␤-induced events and late phenomena related to neuron death. BACE1 levels became elevated in parallel with amyloid burden in each APP transgenic, starting early in 5XFAD and late in Tg2576. The increase in BACE1 protein occurred without any change in BACE1 mRNA level, indicating a posttranscriptional mechanism. In APP transgenic and AD brains, high BACE1 levels were observed in an annulus around A␤42-positive plaque cores and colocalized with neuronal proteins. These results demonstrate that amyloid plaques induce BACE1 in surrounding neurons at early stages of pathology before neuron death occurs. We conclude that BACE1 elevation is most likely triggered by the amyloid pathway and may drive a positive-feedback loop in AD.

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“…Equal volumes were resolved by 4 to 12% Bis-Tris NuPAGE in MES running buffer (Invitrogen) and proteins electrotransferred to nitrocellulose filter membranes (Hybond-ECL, Amersham Biosciences). Membranes were blocked in 5% nonfat dry milk in Tris-buffered saline (pH 7.6) containing 0.1% Tween-20 and incubated overnight with a rabbit antibody against human ApoE (DAKO, Glostrup, Denmark) followed by goat anti-mouse IgG secondary antibody conjugated to horse- 33,37,38 while immunohistochemistry with mAb 3D6 was used to measure total amyloid load, ie, dense and diffuse plaques combined, which is ϳ10 times higher than the dense plaque load. Brain sections were rinsed in PBS and quenched for endogenous peroxidase by incubation at room temperature for 15 minutes in 1.5% H 2 O 2 in methanol/water (50%, v/v).…”

Section: Analysis Of Human Apoementioning

confidence: 99%

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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β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Increases Amyloid Deposition in Brain Parenchyma but Reduces Cerebrovascular Amyloid Angiopathy in Aging BACE × APP[V717I] Double-Transgenic Mice

Cited by 53 publications

References 45 publications

High β-Secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-β Levels

High β-Secretase Activity Elicits Neurodegeneration in Transgenic Mice Despite Reductions in Amyloid-β Levels

β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis

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

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