Co-aggregation with apolipoprotein E modulates the function of amyloid-β in Alzheimer's disease

Zengjie Xia; Emily E Prescott; Agnieszka Urbanek; Hollie E Wareing; Marianne C King; Anna Olerinyova; Helen Dakin; Tom Leah; Katy A Barnes; Martyna M Matuszyk; Eleni Dimou; Eric Hidari; Yu P Zhang; Jeff Y L Lam; John S H Danial; Michael R Strickland; Hong Jiang; Peter Thornton; Damian C Crowther; Sohvi Ohtonen; Mireia Gómez-Budia; Simon M Bell; Laura Ferraiuolo; Heather Mortiboys; Adrian Higginbottom; Stephen B Wharton; David M Holtzman; Tarja Malm; Rohan T Ranasinghe; David Klenerman; Suman De

doi:10.1038/s41467-024-49028-z

Co-aggregation with apolipoprotein E modulates the function of amyloid-β in Alzheimer's disease

Zengjie Xia
, Emily E Prescott
, Agnieszka Urbanek
, Hollie E Wareing
, Marianne C King
, Anna Olerinyova
, Helen Dakin
, Tom Leah
, Katy A Barnes
, Martyna M Matuszyk
, Eleni Dimou
, Eric Hidari
, Yu P Zhang
, Jeff Y L Lam
, John S H Danial
, Michael R Strickland
, Hong Jiang
, Peter Thornton
, Damian C Crowther
, Sohvi Ohtonen

Mireia Gómez-Budia, Simon M Bell, Laura Ferraiuolo, Heather Mortiboys, Adrian Higginbottom, Stephen B Wharton, David M Holtzman, Tarja Malm, Rohan T Ranasinghe^*, David Klenerman^*, Suman De^*

^*Corresponding author for this work

School of Physics and Astronomy

Research output: Contribution to journal › Article › peer-review

Abstract

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

Original language	English
Article number	4695
Number of pages	18
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-49028-z
Publication status	Published - 1 Jun 2024

Keywords

Neuroglia
Animals
Mice, Transgenic
Humans
Mice
Alzheimer Disease
Apolipoproteins E
Protein isoforms
Female
Male
Apolipoprotein E4
Amyloid beta-peptides
Protein aggregates
Protein aggregation, Pathological

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Xia, Z., Prescott, E. E., Urbanek, A., Wareing, H. E., King, M. C., Olerinyova, A., Dakin, H., Leah, T., Barnes, K. A., Matuszyk, M. M., Dimou, E., Hidari, E., Zhang, Y. P., Lam, J. Y. L., Danial, J. S. H., Strickland, M. R., Jiang, H., Thornton, P., Crowther, D. C., ... De, S. (2024). Co-aggregation with apolipoprotein E modulates the function of amyloid-β in Alzheimer's disease. Nature Communications, 15(1), Article 4695. https://doi.org/10.1038/s41467-024-49028-z

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title = "Co-aggregation with apolipoprotein E modulates the function of amyloid-β in Alzheimer's disease",

abstract = "Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for \textasciitilde{}50\% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.",

keywords = "Neuroglia, Animals, Mice, Transgenic, Humans, Mice, Alzheimer Disease, Apolipoproteins E, Protein isoforms, Female, Male, Apolipoprotein E4, Amyloid beta-peptides, Protein aggregates, Protein aggregation, Pathological",

author = "Zengjie Xia and Prescott, \{Emily E\} and Agnieszka Urbanek and Wareing, \{Hollie E\} and King, \{Marianne C\} and Anna Olerinyova and Helen Dakin and Tom Leah and Barnes, \{Katy A\} and Matuszyk, \{Martyna M\} and Eleni Dimou and Eric Hidari and Zhang, \{Yu P\} and Lam, \{Jeff Y L\} and Danial, \{John S H\} and Strickland, \{Michael R\} and Hong Jiang and Peter Thornton and Crowther, \{Damian C\} and Sohvi Ohtonen and Mireia G{\'o}mez-Budia and Bell, \{Simon M\} and Laura Ferraiuolo and Heather Mortiboys and Adrian Higginbottom and Wharton, \{Stephen B\} and Holtzman, \{David M\} and Tarja Malm and Ranasinghe, \{Rohan T\} and David Klenerman and Suman De",

note = "Funding: This study was supported by the EPSRC grant 2594676 (HEW, SD), Alzheimer{\textquoteright}s Society PhD studentship grant 396 (MM,SW), AMS grants SGL028\textbackslash{}1097 (SMB), Parkinson{\textquoteright}s UK grants F-1301 (H.M.), NIH grants AG047644 (D.M.H.) and NS090934 (D.M.H.), European Research Council Grant Number 669237 (D.K.), the Royal Society (D.K.), Dementia Research UK Pilot Award (S.D.), the UK Dementia Research Institute (DRI) at Cambridge (D.K.), Academy of Medical science springboard award SBF006\textbackslash{}1038 (S.D.) and a UKRI Future Leaders Fellowship (Grant number MR/V023861/1) (A.O., A.U., and S.D.). ",

year = "2024",

month = jun,

day = "1",

doi = "10.1038/s41467-024-49028-z",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Xia, Z, Prescott, EE, Urbanek, A, Wareing, HE, King, MC, Olerinyova, A, Dakin, H, Leah, T, Barnes, KA, Matuszyk, MM, Dimou, E, Hidari, E, Zhang, YP, Lam, JYL, Danial, JSH, Strickland, MR, Jiang, H, Thornton, P, Crowther, DC, Ohtonen, S, Gómez-Budia, M, Bell, SM, Ferraiuolo, L, Mortiboys, H, Higginbottom, A, Wharton, SB, Holtzman, DM, Malm, T, Ranasinghe, RT, Klenerman, D & De, S 2024, 'Co-aggregation with apolipoprotein E modulates the function of amyloid-β in Alzheimer's disease', Nature Communications, vol. 15, no. 1, 4695. https://doi.org/10.1038/s41467-024-49028-z

TY - JOUR

T1 - Co-aggregation with apolipoprotein E modulates the function of amyloid-β in Alzheimer's disease

AU - Xia, Zengjie

AU - Prescott, Emily E

AU - Urbanek, Agnieszka

AU - Wareing, Hollie E

AU - King, Marianne C

AU - Olerinyova, Anna

AU - Dakin, Helen

AU - Leah, Tom

AU - Barnes, Katy A

AU - Matuszyk, Martyna M

AU - Dimou, Eleni

AU - Hidari, Eric

AU - Zhang, Yu P

AU - Lam, Jeff Y L

AU - Danial, John S H

AU - Strickland, Michael R

AU - Jiang, Hong

AU - Thornton, Peter

AU - Crowther, Damian C

AU - Ohtonen, Sohvi

AU - Gómez-Budia, Mireia

AU - Bell, Simon M

AU - Ferraiuolo, Laura

AU - Mortiboys, Heather

AU - Higginbottom, Adrian

AU - Wharton, Stephen B

AU - Holtzman, David M

AU - Malm, Tarja

AU - Ranasinghe, Rohan T

AU - Klenerman, David

AU - De, Suman

N1 - Funding: This study was supported by the EPSRC grant 2594676 (HEW, SD), Alzheimer’s Society PhD studentship grant 396 (MM,SW), AMS grants SGL028\1097 (SMB), Parkinson’s UK grants F-1301 (H.M.), NIH grants AG047644 (D.M.H.) and NS090934 (D.M.H.), European Research Council Grant Number 669237 (D.K.), the Royal Society (D.K.), Dementia Research UK Pilot Award (S.D.), the UK Dementia Research Institute (DRI) at Cambridge (D.K.), Academy of Medical science springboard award SBF006\1038 (S.D.) and a UKRI Future Leaders Fellowship (Grant number MR/V023861/1) (A.O., A.U., and S.D.).

PY - 2024/6/1

Y1 - 2024/6/1

N2 - Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

AB - Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.

KW - Neuroglia

KW - Animals

KW - Mice, Transgenic

KW - Humans

KW - Mice

KW - Alzheimer Disease

KW - Apolipoproteins E

KW - Protein isoforms

KW - Female

KW - Male

KW - Apolipoprotein E4

KW - Amyloid beta-peptides

KW - Protein aggregates

KW - Protein aggregation, Pathological

U2 - 10.1038/s41467-024-49028-z

DO - 10.1038/s41467-024-49028-z

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4695

ER -

Co-aggregation with apolipoprotein E modulates the function of amyloid-β in Alzheimer's disease

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Keywords

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