Accelerated Aβ aggregation in the presence of GM1-ganglioside- accumulated synaptosomes of aged apoE4-knock-in mouse brain

Naoki Yamamoto; Urule Igbabvoa; Yukiko Shimada; Yoshiko Ohno-Iwashita; Mariko Kobayashi; W. Gibson Wood; Shinobu C. Fujita; Katsuhiko Yanagisawa

doi:10.1016/j.febslet.2004.05.037

Accelerated Aβ aggregation in the presence of GM1-ganglioside- accumulated synaptosomes of aged apoE4-knock-in mouse brain

Naoki Yamamoto
, Urule Igbabvoa
, Yukiko Shimada
, Yoshiko Ohno-Iwashita
, Mariko Kobayashi
, W. Gibson Wood
, Shinobu C. Fujita
, Katsuhiko Yanagisawa

Pharmacology

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

71 Scopus citations

Abstract

Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid β-protein (Aβ) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that Aβ aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound Aβ which acts as a seed for Aβ fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4- than the apoE3-knock-in mouse brain. Furthermore, we show that Aβ aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate Aβ aggregation in the brain through an increase in the level of GM1 in neuronal membranes.

Original language	English (US)
Pages (from-to)	135-139
Number of pages	5
Journal	FEBS Letters
Volume	569
Issue number	1-3
DOIs	https://doi.org/10.1016/j.febslet.2004.05.037
State	Published - Jul 2 2004

Bibliographical note

Funding Information:
This study was supported by Grants-in-Aid for Scientific Research on Priority Area (C)-Advanced Brain Science Project from the Ministry of Education, Culture, Sports, Science and Technology and the Organization for Pharmaceutical Safety and Research of Japan, and grant (1P0AG-18357) from the National Institutes of Health, USA.

Keywords

Alzheimer's disease
Amyloid β-protein
Apolipoprotein E
Ganglioside
Lipid raft

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10.1016/j.febslet.2004.05.037

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title = "Accelerated Aβ aggregation in the presence of GM1-ganglioside- accumulated synaptosomes of aged apoE4-knock-in mouse brain",

abstract = "Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid β-protein (Aβ) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that Aβ aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound Aβ which acts as a seed for Aβ fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4- than the apoE3-knock-in mouse brain. Furthermore, we show that Aβ aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate Aβ aggregation in the brain through an increase in the level of GM1 in neuronal membranes.",

keywords = "Alzheimer's disease, Amyloid β-protein, Apolipoprotein E, Ganglioside, Lipid raft",

author = "Naoki Yamamoto and Urule Igbabvoa and Yukiko Shimada and Yoshiko Ohno-Iwashita and Mariko Kobayashi and Wood, \{W. Gibson\} and Fujita, \{Shinobu C.\} and Katsuhiko Yanagisawa",

note = "Funding Information: This study was supported by Grants-in-Aid for Scientific Research on Priority Area (C)-Advanced Brain Science Project from the Ministry of Education, Culture, Sports, Science and Technology and the Organization for Pharmaceutical Safety and Research of Japan, and grant (1P0AG-18357) from the National Institutes of Health, USA.",

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AU - Ohno-Iwashita, Yoshiko

AU - Kobayashi, Mariko

AU - Wood, W. Gibson

AU - Fujita, Shinobu C.

AU - Yanagisawa, Katsuhiko

N1 - Funding Information: This study was supported by Grants-in-Aid for Scientific Research on Priority Area (C)-Advanced Brain Science Project from the Ministry of Education, Culture, Sports, Science and Technology and the Organization for Pharmaceutical Safety and Research of Japan, and grant (1P0AG-18357) from the National Institutes of Health, USA.

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N2 - Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid β-protein (Aβ) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that Aβ aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound Aβ which acts as a seed for Aβ fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4- than the apoE3-knock-in mouse brain. Furthermore, we show that Aβ aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate Aβ aggregation in the brain through an increase in the level of GM1 in neuronal membranes.

AB - Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid β-protein (Aβ) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that Aβ aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound Aβ which acts as a seed for Aβ fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4- than the apoE3-knock-in mouse brain. Furthermore, we show that Aβ aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate Aβ aggregation in the brain through an increase in the level of GM1 in neuronal membranes.

KW - Alzheimer's disease

KW - Amyloid β-protein

KW - Apolipoprotein E

KW - Ganglioside

KW - Lipid raft

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Accelerated Aβ aggregation in the presence of GM1-ganglioside- accumulated synaptosomes of aged apoE4-knock-in mouse brain

Abstract

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Keywords

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