The Interaction between Apolipoprotein E and Alzheimer's Amyloid β-Peptide Is Dependent on β-Peptide Conformation (original) (raw)
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FEBS Letters, 1995
Apolipoprotein E (apoE) has been found in association with several differents types of systemic and cerebral amyloid deposits and the presence of the E4 allele constitutes a risk factor for Alzheimer's disease. It has been shown that apoE binds and promotes the fibrillogenesis in vitro of Alzheimer's amyloid l[Ipeptide, suggesting an important role for apoE in the modulation of amyloidogenesis. Due to the co-localization of apoE with several biochemically distinct amyloid deposits, it has been proposed that apoE plays a general role modulating and/or participating in amyloidosis. In the present study, we show for the first time that apoE, isolated from human plasma, increases fibril formation of synthetic peptides comprising the amyloidogenic sequences of gelsolin amyloid related to familial amyloidosis Finnish type, and amyloid A found in secondary amyloidosis and familial Mediterranean fever. Our results suggest that apoE acts as a general pathological chaperone in various amyloidoses by enhancing the transition from soluble peptides into amyloid-forming, pathological molecules.
European Journal of Biochemistry, 1997
C-terminal fragments of the Alzheimer amyloid peptide (amino acids 29-40 and 29-42) have physico-chemical properties related to those of the fusion peptides of viral proteins and they are able to induce the fusion of liposomes in vitro. We proposed that these properties could mediate a direct interaction of the amyloid peptide with cell membranes and account for part of the cytotoxicity of the amyloid peptide. In view of the epidemiologic and biochemical linkages between the pathology of Alzheimer's disease and apolipoprotein E (apoE) polymorphism, we examined the potential interaction between the three common apoE isoforms and the C-terminal fragments of the amyloid peptide. We show that, at low concentration, only apoE2 and apoE3 are potent inhibitors of the amyloid peptide fusogenic and aggregational properties, whereas the apoE4 isoform has no effect. We further show that the protective effect of apoE is mediated by the formation of stable apoE/amyloid peptide complexes, as determined by tryptophan emission fluorescence measurements and by gel electrophoresis. The interaction specificity between apoE2 and apoE3 and the amyloid fragments is demonstrated here, since other apolipoproteins (e.g. apolipoprotein A-I and A-II), with similar amphipathic structures, do not interact with the amyloid Cterminal fragments. Finally, we show that, reciprocally, the amyloid peptide can interact directly with the apoE2 and apoE3 isoforms to decrease or perturb their normal association with lipids. These data suggest that the 29-40 and 29-42 domains of the amyloid peptide could be critical for the amyloid-apoE interaction, and that apoE2 and apoE3 isoforms, but not apoE4, could play a protective role against the formation of amyloid aggregates and/or against their interaction with cellular membranes.
Peptides, 2002
Amyloid deposits are primarily composed of the amyloid- protein, although other proteins (and metal ions) also have been colocalized to these lesions. The pattern of oxidative modifications in amyloid plaques is very different to that associated with neurofibrillary tangles and neuronal cell bodies, likely reflecting the different composition of these structures, accessibility of oxidants, the generation of oxidants in and around these structures and the intrinsic antioxidant defense systems to protect these structures. Future studies directed at understanding A interactions with other amyloid components, the role of oxidative modifications in stabilizing amyloid deposits and the determination of protease cleavage sites on A may provide mechanistic insights regarding both amyloid formation and removal. (C.S. Atwood). regulation of ␥-secretase proteolytic activity . PS-1 is an integral membrane protein that resides predominantly in intracellular membranous organelles such as the endoplasmic reticulum and Golgi apparatus which are also the identified sites of APP processing . Although A is released as a soluble protein, and is detected in biological fluids and tissue, it aggregates as diffuse amorphous (noncongophilic) deposits and dense, focal (congophilic), extracellular deposits in AD . The deposition of A and numerous other components, into amyloid deposits, is associated with a chronic inflammatory response and oxidative damage (reviewed in ). In this article, we review the composition of amyloid plaques, and the posttranslational modification of these components. Readers are directed to other recent reviews for information on the mechanisms of amyloid formation and clearance .
Biochemistry, 1990
The amyloid 0-protein (1-42) is a major constituent of the abnormal extracellular amyloid plaque that characterizes the brains of victims of Alzheimer's disease. Two peptides, with sequences derived from the previously unexplored C-terminal region of the @protein, 026-33 (H2N-SNKGAIIG-C02H) and 034-42 (H2N-LMVGGVVIA-C02H), were synthesized and purified, and their solubility and conformational properties were analyzed. Peptide 026-33 was found to be freely soluble in water; however, peptide 034-42 was virtually insoluble in aqueous media, including 6 M guanidinium thiocyanate. The peptides formed assemblies having distinct fibrillar morphologies and different dimensions as observed by electron microscopy of negatively stained samples. X-ray diffraction revealed that the peptide conformation in the fibrils was cross-0. A correlation between solubility and 0-structure formation was inferred from FTIR studies: 026-33, when dissolved in water, existed as a random coil, whereas the water-insoluble peptide 034-42 possessed antiparallel @-sheet structure in the solid state. Solubilization of ,834-42 in organic media resulted in the disappearance of 0-structure. These data suggest that the sequence 34-42, by virtue of its ability to form unusually stable @-structure, is a major contributor to the insolubility of the @-protein and may nucleate the formation of the fibrils that constitute amyloid plaque.
Amyloid β binding proteins in vitro and in normal human cerebrospinal fluid
Neuroscience Letters, 1995
A major neuropathological feature of AIzheimer's disease (AD) is the deposition of amyloid p (A@) in the form of senile plaques. The Ap peptide exists both in a P-pleated sheet fibrillar form in amyloid deposits and as a normal soluble protein in biological fluids. Numerous proteins have been identified immunohistochemically to be associated with senile plaques, where A@ is the major constituent. Some of the latter have also been suggested to be carriers of the normal soluble A/3 (SW) including apolipoprotein J (apoJ), apolipoprotein E (apoE) and transthyretin (TTR). We have found, using several different methods, that numerous proteins can bind synthetic A/? peptides when high concentrations are used; however, using an affinity anti-s@ column we confirm that apoJ is the major binding protein in pooled human cerebrospinal fluid. On the other hand it is known that apoE co-purifies with A#? biochemicaily extracted from senile plaques. In AD tissue there may be a change in the major apolipoprotein binding A@ from apoJ to apoE.
Biochemistry, 2014
Deposition of amyloid-β (Aβ) in Alzheimer's disease (AD) is strongly correlated with the APOE genotype. However, the role of apolipoprotein E (apoE) in Aβ aggregation has remained unclear. Here we have used different apoE preparations, such as recombinant protein or protein isolated from cultured astrocytes, to examine the effect of apoE on the aggregation of both Aβ 1−40 and Aβ 1−42. The kinetics of aggregation, measured by the loss of fluorescence of tetramethylrhodamine-labeled Aβ, is shown to be dramatically slowed by the presence of substoichiometric concentrations of apoE. Using these concentrations, we conclude that apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth. At higher apoE concentrations, the protein also binds to Aβ fibrils, resulting in fibril stabilization and a slower rate of fibril growth. The aggregation of Aβ 1−40 is dependent on the apoE isoform, being the most dramatic for apoE4 and less so for apoE3 and apoE2. Our results indicate that the detrimental role of apoE4 in AD could be related to apoEinduced stabilization of the soluble but cytotoxic oligomeric forms and intermediates of Aβ, as well as fibril stabilization. A lzheimer's disease (AD) is characterized by the extracellular accumulation of amyloid-β (Aβ) in compact plaques of the brain. These plaques are hypothesized to be directly related to the development of this disease. There are, however, many additional factors implicated in the development of Alzheimer's disease. Among these is the protein apolipoprotein E4 (apoE4), which is known to be the major genetic risk factor for developing late-onset AD. 1,2 How apoE4 influences the pathology of AD is not fully understood, but a large body of literature points to its role in influencing the aggregation and clearance of Aβ from the brain. 3−11 The presence of both soluble complexes 12−14 and insoluble deposits 4,15 of the apoE−Aβ complex in the mouse and human brain suggests the importance of a direct interaction between apoE and Aβ in the development of AD. There are many conflicting reports in the literature about the nature of this interaction. 1,3,5,6,9,11,16−18 We believe that these apparent contradictions can be traced to the complex properties of both apoE and Aβ themselves. For example, most reported biophysical experiments have used recombinant lipid-free apoE that is both structurally and functionally different from apoE complexed with lipids. 19−21 Lipid-free apoE has a compact structure comprising a four-helix bundle N-terminal domain and a C-terminal helical domain that displays extensive interactions with the N-terminal domain. 20 There is no highresolution structure available for lipidated apoE, but a lowresolution structure obtained by X-ray diffraction of dipalmitoylphosphatidylcholine (DPPC)-bound apoE particles shows that the DPPC−apoE complex adopts an extended conformation forming a beltlike structure around the lipid core. 21 ApoE lipoproteins derived from cultured cells, plasma, or cerebrospinal fluids vary widely in terms of their content of lipids, sterols, and other associated lipoproteins. Similarly, both common alloforms of Aβ, Aβ 1−40 and Aβ 1−42 , are intrinsically disordered peptides with strong tendencies to aggregate. Thus,