Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman, David M.; Herz, Joachim; Bu, Guojun

doi:10.1101/cshperspect.a006312

Cited by 681 publications

(641 citation statements)

References 224 publications

(274 reference statements)

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“…One of these differences is the relative affinity of each isoform for the lipoprotein receptors at the cell surface, thereby affecting the total amount of cholesterol imported 14. Upon receptor‐mediated endocytosis, the ApoE‐containing HDL‐like particles are transported to lysosomes, where they are hydrolyzed.…”

Section: Resultsmentioning

confidence: 99%

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

et al. 2015

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In addition to the appearance of senile plaques and neurofibrillary tangles, Alzheimer's disease (AD) is characterized by aberrant lipid metabolism and early mitochondrial dysfunction. We recently showed that there was increased functionality of mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM), a subdomain of the ER involved in lipid and cholesterol homeostasis, in presenilin‐deficient cells and in fibroblasts from familial and sporadic AD patients. Individuals carrying the ε4 allele of apolipoprotein E (ApoE4) are at increased risk for developing AD compared to those carrying ApoE3. While the reason for this increased risk is unknown, we hypothesized that it might be associated with elevated MAM function. Using an astrocyte‐conditioned media (ACM) model, we now show that ER–mitochondrial communication and MAM function—as measured by the synthesis of phospholipids and of cholesteryl esters, respectively—are increased significantly in cells treated with ApoE4‐containing ACM as compared to those treated with ApoE3‐containing ACM. Notably, this effect was seen with lipoprotein‐enriched preparations, but not with lipid‐free ApoE protein. These data are consistent with a role of upregulated MAM function in the pathogenesis of AD and may help explain, in part, the contribution of ApoE4 as a risk factor in the disease.

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Section: Resultsmentioning

confidence: 99%

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

et al. 2015

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“…This observation is in agreement with the idea that APOEε4 affects primarily the levels of Ab peptide (thereby leading to a higher plaque burden, a higher risk of AD, and an earlier age of symptom onset), but it has no or little effect on pathologic processes downstream of Ab. 25 Although they should be viewed as preliminary, given the modest sample size and that complex interactions among the variables may not have been adequately modeled, some interesting observations can be extracted from the secondary analyses of rate of change of markers over time. The fact that the increase in number of dystrophic neurites seems to slow down in the longest duration cases might suggest that the neurites, or the neurons that give rise to them, were lost in the longduration cases.…”

Section: Discussionmentioning

confidence: 99%

“…The APOEε4 allele is the strongest known genetic risk factor for the development of sporadic AD, and it does so by promoting the accumulation of amyloid b (Ab) peptide and its deposition in plaques (reviewed in Holtzman et al 25 ), but whether plaques from APOEε4 carriers are more toxic to the surrounding neuropil than plaques from APOEε4 noncarriers remains unclear. There were 21 APOEε4 carriers and 19 APOEε4 noncarriers among the 40 AD subjects and 3 APOEε4 carriers and 6 APOEε4 noncarriers among the nine CTRL subjects in this sample.…”

Section: Lack Of Effect Of Apoeε4 Allele In the Accrual Of Plaque-assmentioning

confidence: 99%

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Serrano-Pozo

Betensky

Frosch

et al. 2016

The American Journal of Pathology

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Amyloid (senile) plaques, one of the two pathologic hallmarks of Alzheimer disease (AD), are associated with dystrophic neurites and glial responses, both astrocytic and microglial. Although plaque burden remains relatively stable through the clinical course of AD, whether these features of local plaque toxicity continue to worsen over the course of the disease is unclear. We performed an unbiased plaque-centered quantification of SMI312 þ dystrophic neurites, GFAP þ reactive astrocytes, and IBA1 þ and CD68 þ activated microglia in randomly selected dense-core (Thioflavin-S þ ) plaques from the temporal neocortex of 40 AD subjects with a symptom duration ranging from 4 to 20 years, and nine nondemented control subjects with dense-core plaques. Dystrophic neurites (Kendall t Z 0.34, P Z 0.001), reactive astrocytes (Kendall t Z 0.30, P Z 0.003), and CD68 þ (Kendall t Z 0.48, P < 0.0001), but not IBA1 microglia (Kendall t Z 0.045, P Z 0.655), exhibited a significant positive correlation with symptom duration. When excluding control subjects, only the positive association between CD68 þ microglia and symptom duration remained significant (Kendall t Z 0.39, P Z 0.0003). The presence of the APOEε4 allele did not affect these results. We conclude that plaques exert an increasing toxicity in the surrounding neuropil over the clinical course of AD, thereby potentially contributing to cognitive decline. (Am J Pathol 2016, 186: 375e384; http://dx

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“…Many APP‐transgenic mouse models have been crossed to other transgenic/knockout mouse models to study their effect on amyloid deposition/clearance (Holtzman et al ., 2012). However, in these studies, an effect on hAPP transgene expression could not be excluded as no antibody was available that enabled clear discrimination between human and murine APP.…”

Section: Discussionmentioning

confidence: 99%

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

et al. 2016

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SummaryAlzheimer's disease (AD) is histopathologically characterized by neurodegeneration, the formation of intracellular neurofibrillary tangles and extracellular Aβ deposits that derive from proteolytic processing of the amyloid precursor protein (APP). As rodents do not normally develop Aβ pathology, various transgenic animal models of AD were designed to overexpress human APP with mutations favouring its amyloidogenic processing. However, these mouse models display tremendous differences in the spatial and temporal appearance of Aβ deposits, synaptic dysfunction, neurodegeneration and the manifestation of learning deficits which may be caused by age‐related and brain region‐specific differences in APP transgene levels. Consequentially, a comparative temporal and regional analysis of the pathological effects of Aβ in mouse brains is difficult complicating the validation of therapeutic AD treatment strategies in different mouse models. To date, no antibodies are available that properly discriminate endogenous rodent and transgenic human APP in brains of APP‐transgenic animals. Here, we developed and characterized rat monoclonal antibodies by immunohistochemistry and Western blot that detect human but not murine APP in brains of three APP‐transgenic mouse and one APP‐transgenic rat model. We observed remarkable differences in expression levels and brain region‐specific expression of human APP among the investigated transgenic mouse lines. This may explain the differences between APP‐transgenic models mentioned above. Furthermore, we provide compelling evidence that our new antibodies specifically detect endogenous human APP in immunocytochemistry, FACS and immunoprecipitation. Hence, we propose these antibodies as standard tool for monitoring expression of endogenous or transfected APP in human cells and APP expression in transgenic animals.

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Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Cited by 681 publications

References 224 publications

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

Plaque-Associated Local Toxicity Increases over the Clinical Course of Alzheimer Disease

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

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