Noninfarct vascular dementia and Alzheimer dementia spectrum

Emery, Vincent C.; Gillie, Edward; Smith, Joseph A.

doi:10.1016/j.jns.2004.11.016

Cited by 13 publications

(14 citation statements)

References 32 publications

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“…We found that in APP23/ABCA1 Ϫ/Ϫ versus APP23/ABCA1 ϩ/ϩ mice, the lack of ABCA1 resulted in an increase of soluble (RIPA-extractable) A␤ 40 and A␤ 42 , although the difference did not reach statistical significance ( Fig. 2A).…”

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 90%

“…C, insoluble A␤ 40 and A␤ 42 as measured by ELISA were increased in APP23/ABCA1 Ϫ/Ϫ versus APP23/ABCA1 ϩ/ϩ mice. D, the percent soluble A␤ 40 and A␤ 42 as a fraction of total A␤ (soluble and insoluble) was elevated in APP23/ABCA1 ϩ/ϩ versus APP23/ABCA1 Ϫ/Ϫ mice. E, insoluble apoE was determined by WB of formic acid-extracted brain homogenate (see under "Materials and Methods").…”

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 95%

“…We measured levels of A␤ 40 and A␤ 42 in both RIPA-soluble and -insoluble brain Ϫ/ϩ mice (het) is 2-fold less than in APP23/ABCA1 ϩ/ϩ (wt) mice. There is no change in the expression of human APPsw (hAPP) as detected by 6E10 antibody.…”

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 99%

“…Ϫ/Ϫ versus APP23/ABCA1 ϩ/ϩ and APP23/ABCA1 ϩ/Ϫ mice; however, the difference did not reach statistical significance. B, insoluble A␤ total (A␤ 40 ϩ A␤ 42 ) was determined by WB of formic acid-extracted A␤ by using 6E10 antibody that recognizes both A␤ 40 Ϫ/Ϫ ). The bands were quantified, and the level of A␤ total was normalized to the level of full-length human APP (APPfl).…”

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 99%

“…2A). We also examined the level of insoluble (formic acid extractable) A␤ by WB using 6E10 antibody, which recognizes both A␤ 40 and A␤ 42 (referred as A␤ total in Fig. 2B).…”

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 99%

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Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice

Koldamova

Staufenbiel

Lefterov

2005

Journal of Biological Chemistry

323

285

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animals, supports the conclusion that the ABCA1 deficiency increases amyloid deposition. These results suggest that ABCA1 plays a role in the pathogenesis of parenchymal and cerebrovascular amyloid pathology and thus may be considered a therapeutic target in AD.The deposition of A␤ 3 in the brain parenchyma and vessels is a pathological hallmark of AD, and it is believed that A␤ plays a central role in the pathogenesis of the neuronal dysfunction and cognitive impairment during the progression of the disease. Unlike familial early onset forms of AD, which are caused by mutations in APP or presenilins, the cause of late onset AD (LOAD) remains unknown. The inheritance of the apoE ⑀4 allele (apoE4) is considered a strong and independent risk factor of AD and is associated with increased neuritic plaques and CAA (1-3). It has been reported that in APP transgenic mice the disruption of the apoE gene causes a dramatic reduction of parenchymal amyloid plaques and CAA (4 -6).Two independent groups have reported recently that the lack of ABCA1 causes Ͼ75% reduction of apoE protein level in the brain of ABCA1 Ϫ/Ϫ mice (7, 8). The decreased apoE level in the central nervous system was not related to apoE gene expression but likely was caused by increased metabolism of abnormally lipidated apoE containing lipoprotein (8). ABCA1 is a major regulator of cholesterol efflux, HDL metabolism, and reverse cholesterol transport (9, 10). Mutations in the ABCA1 gene cause severe HDL deficiencies, the most prominent of which is Tangier disease, which is characterized by the virtual absence of apoA-I and HDL, the accumulation of cholesterol in cells, and the prevalence of atherosclerosis (11-13). The transcriptional activation of ABCA1, and other genes involved in cholesterol metabolism, is controlled by nuclear liver X receptors ␣ and ␤ LXR␣/␤ (14, 15). Target genes of LXR␣/␤ have already been implicated in the control of APP proteolytic processing (16 -18). The effect was attributed primarily but not only to ABCA1. It was also reported that a set of genetic variants of ABCA1 modifies the risk for AD (19,20) in Scottish, Swedish, and English populations, although another study of American and UK populations found that ABCA1 variants do not appear to influence the risk of LOAD (21). Experiments with any of those genetic variants or complex AD model systems (APP transgenic/ABCA1 knock-out animals for example) have not been reported, and so there is no definitive conclusion about the role of ABCA1 in AD. To determine further the effect of ABCA1 on amyloid deposition, we used APP23 transgenic mice in which APPsw is expressed only in the brain. These mice develop compact amyloid plaques in brain parenchyma and CAA, reminiscent of the pathological features of AD (22)(23)(24). In this study APP23 mice were bred to ABCA1 knock-out mice, and A␤-related pathology was evaluated in APP23 mice with intact (APP23/ABCA1 ϩ/ϩ ) or disrupted (APP23/ABCA1 Ϫ/Ϫ ) ABCA1 gene. Our results demonstrate that in APP23 mice the lack of ABCA1 increases A␤ deposi...

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Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 90%

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 95%

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 99%

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 99%

“…2A). We also examined the level of insoluble (formic acid extractable) A␤ by WB using 6E10 antibody, which recognizes both A␤ 40 and A␤ 42 (referred as A␤ total in Fig. 2B).…”

Section: Lack Of Abca1 Increases the Level Of Insoluble A␤ In 13-montmentioning

confidence: 99%

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Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice

Koldamova

Staufenbiel

Lefterov

2005

Journal of Biological Chemistry

323

285

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La « maladie d’Alzheimer » commune : un syndrome hétérogène avant tout vasculaire ?

Henry–Feugeas

2008

Bio trib. mag.

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Alzheimer disease: are we intervening too late?

Emery¹

2011

J Neural Transm

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The affirmative position is argued in response to the question of whether intervention in the disease course of Alzheimer disease (AD) occurs too late. AD is not a singular, homogeneous disease, but rather a final common pathway or end-point that can be arrived at through multiple routes. As part of the affirmative argument, there is a delineation of two long-term trajectories leading to AD: (1) normal elderly progression to AD, and (2) depressed elderly progression to AD. In documenting normal elderly devolution into AD, two "normal" elderly pre-AD or prodromal stages are discussed: age-associated memory impairment (AAMI) and mild cognitive impairment (MCI). Data are provided evidencing significantly high conversion rates from these pre-AD stages to actual AD. Using the same paradigmatic approach that is used in documenting normal elderly decline into AAMI and MCI with eventual conversion to AD; there is explication of depressed elderly conversion to AD. The long-term, multiphasic disease progression of major depression without dementia to depressive dementia to final conversion to AD is brought into focus as another example of why intervention must occur prior to actual conversion to AD. Depression is defined as a cognitive syndrome and risk factor for AD requiring aggressive targeted intervention. AD does not just come suddenly out of nowhere. First intervention must occur during the pre-AD phases in an attempt to prevent, delay, and interrupt long-term neurodegenerative processes involved in both normal elderly and depressed elderly conversion to AD. A primary strategy proposed is to delay onset of AD. Population statistics indicate that if AD is delayed by a modest 1 year, there would be 9.5 million fewer cases by 2050, resulting in significant reduction in burden of disease. Data show early intervention with cognitive stimulation (mental exercise), physical exercise, aggressive treatment of AD risk factors and excess disability, psychotherapy, and other nonpharmacological interventions in combination with each other and/or with medications can result in delay of onset of AD. First intervention at time of diagnosis of AD is too late, when by definition, final conversion to AD has already occurred. When we have knowledge to successfully intervene earlier, why would we not want to do so.

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Noninfarct vascular dementia and Alzheimer dementia spectrum

Cited by 13 publications

References 32 publications

Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice

Lack of ABCA1 Considerably Decreases Brain ApoE Level and Increases Amyloid Deposition in APP23 Mice

La « maladie d’Alzheimer » commune : un syndrome hétérogène avant tout vasculaire ?

Alzheimer disease: are we intervening too late?

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