High‐affinity multivalent interactions between apolipoprotein E and the oligomers of amyloid‐β

Ghosh, Swagatha; Sil, Timir Baran; Dolai, Subhrajyoti; Garai, Kanchan

doi:10.1111/febs.14988

Cited by 25 publications

(20 citation statements)

References 65 publications

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“…The effect is pronounced also at highly sub-stoichiometric ratios of ApoE versus IAPP indicating that ApoE targets oligomeric nuclei in preference of the monomer. An avid binding of ApoE to Aβ oligomers but not to monomer has recently been described [66], and simply based on the stoichiometry, a similar mechanism can be anticipated also here. The level of the plateau at steady state was also found to be affected in an unexpected manner, and regarding all ApoE variants, a significant increase in the ThT response was observed in the presence of low ApoE concentrations.…”

Section: Discussionsupporting

confidence: 71%

Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

et al. 2020

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Apolipoprotein E (ApoE) has become a primary focus of research after the discovery of its strong linkage to Alzheimer’s disease (AD), where the ApoE4 variant is the highest genetic risk factor for this disease. ApoE is commonly found in amyloid deposits of different origins, and its interaction with amyloid-β peptide (Aβ), the hallmark of AD, is well known. However, studies on the interaction of ApoEs with other amyloid-forming proteins are limited. Islet amyloid polypeptide (IAPP) is an amyloid-forming peptide linked to the development of type-2 diabetes and has also been shown to be involved in AD pathology and vascular dementia. Here we studied the impact of ApoE on IAPP aggregation and IAPP-induced toxicity on blood vessel pericytes. Using both in vitro and cell-based assays, we show that ApoE efficiently inhibits the amyloid formation of IAPP at highly substoichiometric ratios and that it interferes with both nucleation and elongation. We also show that ApoE protects the pericytes against IAPP-induced toxicity, however, the ApoE4 variant displays the weakest protective potential. Taken together, our results suggest that ApoE has a generic amyloid-interfering property and can be protective against amyloid-induced cytotoxicity, but there is a loss of function for the ApoE4 variant.

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Section: Discussionsupporting

confidence: 71%

Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

et al. 2020

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“…Therefore, we think that the high affinity of the interaction with the oligomers arises from multivalent binding. The multivalent binding might involve oligomeric forms of IAPP and the multiple binding sites on Hsp70, similar to what has been proposed earlier for the interaction between apolipoprotein E and the oligomers of amyloid-β (51). While the polypeptide substrates are believed to bind to the canonical substrate binding cleft in the substrate binding domain, the surface of the Hsp70 proteins are capable of interacting with multitude of cochaperone proteins (33).…”

Section: Discussionsupporting

confidence: 57%

Hsp70 inhibits aggregation of Islet amyloid polypeptide by binding to the heterogeneous prenucleation oligomers

Chilukoti

Sahoo

Deepa

et al. 2020

Preprint

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Molecular chaperone Hsp70 plays important roles in the pathology of amyloid diseases by inhibiting aberrant aggregation of proteins. However, mechanism of the interactions of Hsp70 with the amyloidogenic intrinsically disordered proteins (IDPs) is not clear. Here, we use Hsp70 from different organisms to show that it inhibits aggregation of Islet amyloid polypeptide (IAPP) at substoichiometric concentrations even in absence of ATP. The effect is found to be the strongest if Hsp70 is added in the beginning of aggregation but progressively less if added later, indicating role of Hsp70 in preventing primary nucleation possibly via interactions with the prefibrillar oligomers of IAPP. Fluorescence Correlation Spectroscopy (FCS) measurements of the solutions containing fluorescently labelled Hsp70 and IAPP exhibit fluorescence bursts suggesting formation of heterogeneous complexes of oligomeric IAPP binding to multiple molecules of Hsp70. Size exclusion chromatography and field flow fractionation are then used to fractionate the smaller complexes.Multiangle light scattering and FCS measurements suggest that these complexes comprise of monomers of Hsp70 and small oligomers of IAPP. However, concentration of the complexes is measured to be a few nanomolar amidst several µmolar of free Hsp70 and IAPP. Hence, our results indicate that Hsp70 interacts poorly with the monomers but strongly with oligomers of IAPP. This is likely a common feature of the interactions between the chaperones and the amyloidogenic IDPs.While strong interactions with the oligomers prevent aberrant aggregation, poor interaction with the monomers avert interference with the functions of the IDPs.

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“…Lipidated apoE is known to increase the amount of Aβ oligomers in AD patients 124 . A recent study shows that Aβ oligomers strongly interact with the full‐length apoE than small segments of apoE, suggesting that the high binding affinity is mediated via multivalent interactions 125 …”

Section: Mechanism Of Toxicity Mediated By Aβ Oligomersmentioning

confidence: 99%

Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease

Madhu

Mukhopadhyay

2021

J of Cellular Biochemistry

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Soluble oligomers of amyloid-β (Aβ) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aβ oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aβ oligomers based on their morphology, size, and structural reactivity toward the conformationspecific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aβ oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aβ oligomers such as N-methyl-D-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aβ oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aβ by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncover potential targets for designing AD therapeutics.

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High‐affinity multivalent interactions between apolipoprotein E and the oligomers of amyloid‐β

Cited by 25 publications

References 65 publications

Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

Hsp70 inhibits aggregation of Islet amyloid polypeptide by binding to the heterogeneous prenucleation oligomers

Distinct types of amyloid‐β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease

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