Differential pattern of β-amyloid, amyloid precursor protein and apolipoprotein E expression in cortical senile plaques

Apolipoprotein E (apoE), a protein genetically linked to the incidence of Alzheimer's disease, forms SDS-stable complexes in vitro with β-amyloid peptide (Aβ), the primary component of senile plaques. In the present study, we investigated whether apoE was able to bind full-length Aβ precursor protein (APP). Using a maltose-binding-protein–APP fusion protein and human very-low-density lipoprotein (VLDL), we detected an interaction of apoE with APP that was inhibited by Aβ or anti-apoE antibody. Saturation-binding experiments indicated a single binding equilibrium with an apparent 1:1 stoichiometry and a dissociation constant of 15 nM. An interaction was also observed using apoE from cerebrospinal fluid or delipidated VLDL, as well as recombinant apoE. APP·apoE complexes were SDS-stable, and their formation was not inhibited by reducing conditions; however, they were dissociated by SDS under reducing conditions. ApoE·APP complexes formed high-molecular-mass aggregates, and competition experiments suggested that amino acids 14–23 of Aβ are responsible for complex-formation. Finally, no differences were found when studying the interaction of APP with apoE3 or apoE4. Taken together, our results demonstrate that apoE may form stable complexes with the Aβ moiety of APP with characteristics similar to those of complexes formed with isolated Aβ, and suggest the intriguing possibility that apoE–APP interactions may be pathologically relevant in vivo.

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Apolipoprotein E alters the processing of the β-amyloid precursor protein in APPV717F transgenic mice

Brain Research ◽

10.1016/s0006-8993(02)03437-6 ◽

2002 ◽

Vol 955 (1-2) ◽

pp. 191-199 ◽

Cited By ~ 18

Author(s):

Jean-Cosme Dodart ◽

Kelly R Bales ◽

Edward M Johnstone ◽

Sheila P Little ◽

Steven M Paul

Keyword(s):

Transgenic Mice ◽

Amyloid Precursor Protein ◽

Apolipoprotein E ◽

Precursor Protein ◽

Β Amyloid

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A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition

Biological Psychiatry ◽

10.1016/j.biopsych.2019.04.026 ◽

2019 ◽

Vol 86 (3) ◽

pp. 208-220 ◽

Cited By ~ 9

Author(s):

Darrell Sawmiller ◽

Ahsan Habib ◽

Huayan Hou ◽

Takashi Mori ◽

Anran Fan ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Apolipoprotein E ◽

Precursor Protein ◽

Β Amyloid

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Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

The Journal of Cell Biology ◽

10.1083/jcb.200207113 ◽

2003 ◽

Vol 160 (1) ◽

pp. 113-123 ◽

Cited By ~ 695

Author(s):

Robert Ehehalt ◽

Patrick Keller ◽

Christian Haass ◽

Christoph Thiele ◽

Kai Simons

Keyword(s):

Amyloid Precursor Protein ◽

Lipid Rafts ◽

Senile Plaques ◽

Precursor Protein ◽

Amyloid Peptide ◽

Cross Linking ◽

Dependent Manner ◽

Dynamic Interactions ◽

Β Amyloid ◽

Aβ Generation

Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.

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The effect of cannabinoids on APP, BACE1, and ApoE mRNA expression

SURG Journal ◽

10.21083/surg.v7i1.2852 ◽

2014 ◽

Vol 7 (1) ◽

pp. 47-55

Author(s):

Navjit Brar

Keyword(s):

Amyloid Precursor Protein ◽

Apolipoprotein E ◽

Mrna Expression ◽

Cell Line ◽

Cb1 Receptor ◽

Precursor Protein ◽

Mrna Levels ◽

Β Amyloid ◽

Apoe Mrna ◽

The Brain

Alzheimer's disease (AD) is an age-related neurodegenerative condition associated with cognitive decline. The pathological hallmark of this disease is the deposition of β-amyloid protein plaques (Aβ) in the brain, which evoke neuronal cell death and impair inter-neuronal communication. Past studies have suggested that cannabinoids reduce the levels of Aβ in the brain; however, little is known about the mechanisms involved in this process. In this study, the SH-SY5Y cell line was first examined for expression of amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1), and apolipoprotein E (ApoE), genes involved in Aβ production and clearance. All three genes were expressed and detected in the cell line. We then observed the effects of the endocannabinoid anandamide, a CB1 receptor agonist, on the mRNA expression of APP, BACE1, and ApoE in SH-SY5Y cells. After 48h exposure to anandamide, mRNA levels of APP and BACE1 significantly decreased, which could contribute to reduced Aβ levels. The mechanism of action by which anandamide reduces mRNA levels of APP and BACE1 should be further investigated. ApoE mRNA levels were not found to be significantly changed, suggesting that anandamide does not affect mRNA expression of this gene. The effects of cannabinoids on ApoE levels should be further studied as the effects may occur at a level different from mRNA expression and may even occur via a pathway unrelated to CB1 receptor activation. Keywords: Alzheimer’s disease; β-amyloid; anandamide; amyloid precursor protein; beta-site APP cleaving enzyme 1; apolipoprotein E

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