Use of Fused Circulations to Investigate the Role of Apolipoprotein E as Amyloid Catalyst and Peripheral Sink in Alzheimer's Disease

Nilsson, Lars; Gografe, Sylvia; Costa, David Antônio da; Hughes, Tiffany F.; Dressler, David; Potter, Huntington

doi:10.3727/194982412x13462021398010

Cited by 10 publications

(11 citation statements)

References 39 publications

(52 reference statements)

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“…ΔR ct values due to the nonspecific binding were negligible compared to ΔR ct detected upon the binding between Aβ and ApoE on the surface. This result was in parallel with the reported strong affinity between ApoE isoforms and Aβ peptides …”

Section: Resultssupporting

confidence: 88%

Electrochemical Detection of Isoform‐Specific Interaction between Apolipoprotein E and Amyloid‐β

Jin

Noroozifar

et al. 2018

ChemElectroChem

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Alzheimer's disease (AD) is characterized by the formation of neurofibrillary tangles (NFTs) including amyloid-β (Aβ) in the brain. Apolipoprotein E (ApoE) plays a key role in the homeostasis of cholesterol and other lipids in blood circulation. The interaction between ApoE and Aβ has been implicated in the pathological progression of AD. In this study, the interaction of three isoforms of ApoE4, ApoE3 and ApoE2 with Aβ 1-40 and Aβ 1-42 peptides was investigated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Interactions between Aβ peptides and ApoE isoforms were determined by monitoring the changes in ΔR ct of Nyquist plots. The affinity between Aβ 1-40 and Aβ 1-42 and ApoE isoforms interpreted from EIS data followed the trend: ApoE4 > ApoE3 > ApoE2. Using surface plasmon resonance (SPR), the binding affinity (K D ) constants for the interaction of ApoE4 with Aβ 1-40 and Aβ 1-42 peptides were determined as 185 � 21 nM and 156 � 18 nM, respectively, in agreement with our electrochemical results. Our proof-of-principle study demonstrates that EIS provides a promising platform for the investigation of protein-protein interactions implicated in AD.

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Section: Resultssupporting

confidence: 88%

Electrochemical Detection of Isoform‐Specific Interaction between Apolipoprotein E and Amyloid‐β

Jin

Noroozifar

et al. 2018

ChemElectroChem

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“…It is unlikely that changes in Aβ production, degradation, or transport across BBB play dominant roles in the reduction of brain Aβ of the parabiotic AD mice, as there were no significant changes in the expression of APPfl, CTF-α, CTF-β, BACE1, IDE, NEP, LRP-1, and RAGE. A recent study shows that parabiosis between APPswe/PS1 mouse with ApoE gene and APPswe/PS1 mouse without ApoE gene did not reduce compact plaque burden in the brain of APPswe/PS1 mice with the ApoE gene [ 31 ]; suggesting that the systematic inflammation or immune responses induced by the parabiosis surgery would not be responsible for the large reduction of brain Aβ burden observed in the present study. In addition, both acute and chronic systematic inflammation are suggested to accelerate but not halt Aβ deposition and disease progress of AD [ 13 , 14 , 19 ].…”

Section: Discussionmentioning

confidence: 52%

“…The age-matched female Wt ( n = 8) and Tg mice ( n = 8) without parabiosis were used in parallel as controls. The parabiosis was performed following procedures as previously described [ 31 ]. Briefly, animals were anesthetized with ketamine (100 mg/kg), xylazine (20 mg/kg), and acepromazine (3 mg/kg), and placed in a parallel orientation.…”

Section: Methodsmentioning

confidence: 99%

Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease

et al. 2015

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Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis. We found that blood Aβ levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected 125I labeled Aβ40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aβ derived from the brain can be cleared in the periphery. Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1477-1) contains supplementary material, which is available to authorized users.

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“…We also introduced apoE itself into the circulation via parabiosis and found that it induced amyloid clearance without entering the brain in AD model mice [38]. Thus the “Peripheral Sink Hypothesis” became a viable alternative or addition to the Amyloid Cascade Hypothesis, with apoE potentially playing an additional role as an A β -binding peripheral protein.…”

Section: Background: Apoe In Aβ/amyloid Clearancementioning

confidence: 99%

Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade

Potter

Wısnıewskı

2012

International Journal of Alzheimer's Disease

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The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.

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Use of Fused Circulations to Investigate the Role of Apolipoprotein E as Amyloid Catalyst and Peripheral Sink in Alzheimer's Disease

Cited by 10 publications

References 39 publications

Electrochemical Detection of Isoform‐Specific Interaction between Apolipoprotein E and Amyloid‐β

Electrochemical Detection of Isoform‐Specific Interaction between Apolipoprotein E and Amyloid‐β

Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease

Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade

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