Apolipoprotein E and β-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent

Beffert, Uwe; Cohn, Jeffrey S.; Petit-Turcotte, Caroline; Tremblay, Michel J.; Aumont, Nicole; Ramassamy, Charles; Davignon, Jean; Poirier, Judes

doi:10.1016/s0006-8993(99)01894-6

Cited by 129 publications

(85 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reports of isoformdependent differences in apoE levels in CSF have been inconsistent, most probably because of methodological differences in sample collection and analysis. However, several reports have consistently documented lower apoE levels in the hippocampus of AD patients who are 4 carriers (Beffert et al, 1999, Poirier, 2008. The cumulative effect of this significant decrease in apoE4 levels on brain A␤ burden over time appears to be quite dramatic, since the level of brain A␤/amyloid burden was quite substantial in PDAPP/TRE4 mice (Fig.…”

Section: Discussionmentioning

confidence: 88%

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Bales¹,

Liu²,

Wu³

et al. 2009

J. Neurosci.

253

202

View full text Add to dashboard Cite

To investigate the role of human apolipoprotein E (apoE) on A␤ deposition in vivo, we crossed PDAPP mice lacking mouse Apoe to targeted replacement mice expressing human apoE (PDAPP/TRE2, PDAPP/TRE3, or PDAPP/TRE4). We then measured the levels of apoE protein and A␤ peptides in plasma, CSF, and brain homogenates in these mice at different ages. We also quantified the amount of brain A␤ and amyloid burden in 18-month-old mice. In young PDAPP/TRE4 mice that were analyzed at an age before brain A␤ deposition, we observed a significant decrease in the levels of apoE in CSF and brain when compared with age-matched mice expressing either human E2 or E3. The brain levels of A␤42 in PDAPP/TRE4 mice were substantially elevated even at this very early time point. In older PDAPP/TRE4 mice, the levels of insoluble apoE protein increased in parallel to the dramatic rise in brain A␤ burden, and the majority of apoE was associated with A␤. In TRE4 only mice, we also observed a significant decrease in the level of apoE in brain homogenates. Since the relative level of apoE mRNA was equivalent in PDAPP/TRE and TRE only mice, it appears that post-translational mechanisms influence the levels of apoE protein in brain (E4 Ͻ E3 Ͻ Ͻ E2), resulting in early and dramatic apoE isoform-dependent effects on brain A␤ levels (E4 Ͼ Ͼ E3 Ͼ E2) that increase with age. Therapeutic strategies aimed at increasing the soluble levels of apoE protein, regardless of isoform, may effectively prevent and (or) treat Alzheimer's disease.

show abstract

Section: Discussionmentioning

confidence: 88%

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Bales¹,

Liu²,

Wu³

et al. 2009

J. Neurosci.

253

202

View full text Add to dashboard Cite

show abstract

“…Amyloid imaging and autopsy studies have demonstrated a similar topographic distribution, but with more extensive and greater Aβ plaque deposition in isocortical regions, including frontal and parietal lobes, in carriers relative to noncarriers (23,54). Thus, the less-prominent atrophy of these brain regions in ε4 carriers may be mediated through other mechanisms, perhaps related to differential response of isocortical neurons to AD pathology or even developmental influences of APOE genotype, which may relate to individual differences in cognitive performance (55,56), neuroanatomy (57), or brain function (52) at a young age.…”

Section: Discussionmentioning

confidence: 92%

Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

Wolk

Dickerson²

2010

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

216

178

View full text Add to dashboard Cite

The ε4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer's disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the ε4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of ε4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer's Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.cognition | neuroimaging | dementia | cortical thickness | medial temporal lobe

show abstract

“…In plasma, apoE4 preferentially binds to large, triglyceride-rich, very low-density lipoproteins and is more rapidly catabolized by the liver, thus leading to low steady state plasma levels. The effect of the 4 allele on the locally synthesized CNS apoE protein levels is less clear with multiple conflicting reports showing either reduced levels (Bertrand et al, 1995;Beffert et al, 1999;Glöckner et al, 2002;Poirier, 2005;Ramaswamy et al, 2005), no change Fryer et al, 2005) or increases (Fukumoto et al, 2003) in apoE from both AD patient CNS and animal models. In this study, we have extensively analyzed the effect of the 4 allele on apoE levels both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Riddell¹,

Zhou²,

Atchison³

et al. 2008

J. Neurosci.

301

246

View full text Add to dashboard Cite

Inheritance of the apoE4 allele (4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of 4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of 2/2, 3/3, and 4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; 2/2 Ͼ3/3 Ͼ4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the 3/4 mouse brains. ApoE4 represented 30 -40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between 3/3 and 3/4 mice, implying that the reduced levels of total apoE in 3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from 3/4 human astrocytoma or 3/3, 4/4 and 3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from 4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by 4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or A␤ clearance.

show abstract

Apolipoprotein E and β-amyloid levels in the hippocampus and frontal cortex of Alzheimer's disease subjects are disease-related and apolipoprotein E genotype dependent

Cited by 129 publications

References 45 publications

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

HumanAPOEIsoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice

Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Contact Info

Product

Resources

About