Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells

Lai Lei Ting, Hsien Tsung Lu, Shu Fen Yen, Thi Huong Ngo, Fang Yu Tu, I. Shih Tsai, Yi Hua Tsai, Fu Yen Chang, Xiao Jiang Li, Shihua Li, Ching Kuo Lee, Shu Huei Kao, Yu Min Kuo, Yung Feng Lin

研究成果: 雜誌貢獻文章

摘要

A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.
原文英語
期刊Molecular Neurobiology
DOIs
出版狀態已發佈 - 一月 1 2019

指紋

Amyloid beta-Protein Precursor
Alzheimer Disease
Pathology
Amyloid
Protein C
Culture Media
Serum Amyloid A Protein
Brain
Protein Transport
Neuroblastoma
Human Activities
Psychiatry
Cell Differentiation
Cell Survival
Cell Culture Techniques
Genotype
Neurons
Mutation

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

引用此文

Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells. / Ting, Lai Lei; Lu, Hsien Tsung; Yen, Shu Fen; Ngo, Thi Huong; Tu, Fang Yu; Tsai, I. Shih; Tsai, Yi Hua; Chang, Fu Yen; Li, Xiao Jiang; Li, Shihua; Lee, Ching Kuo; Kao, Shu Huei; Kuo, Yu Min; Lin, Yung Feng.

於: Molecular Neurobiology, 01.01.2019.

研究成果: 雜誌貢獻文章

Ting, Lai Lei ; Lu, Hsien Tsung ; Yen, Shu Fen ; Ngo, Thi Huong ; Tu, Fang Yu ; Tsai, I. Shih ; Tsai, Yi Hua ; Chang, Fu Yen ; Li, Xiao Jiang ; Li, Shihua ; Lee, Ching Kuo ; Kao, Shu Huei ; Kuo, Yu Min ; Lin, Yung Feng. / Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells. 於: Molecular Neurobiology. 2019.
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abstract = "A hallmark of Alzheimer’s disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-β (Aβ) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aβ production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-β (CTFβ) and Aβ42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFβ in the total lysates of AD model cells as well as Aβ in the culture media. Consequently, AHI1–APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.",
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T1 - Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer’s Disease Model Cells

AU - Ting, Lai Lei

AU - Lu, Hsien Tsung

AU - Yen, Shu Fen

AU - Ngo, Thi Huong

AU - Tu, Fang Yu

AU - Tsai, I. Shih

AU - Tsai, Yi Hua

AU - Chang, Fu Yen

AU - Li, Xiao Jiang

AU - Li, Shihua

AU - Lee, Ching Kuo

AU - Kao, Shu Huei

AU - Kuo, Yu Min

AU - Lin, Yung Feng

PY - 2019/1/1

Y1 - 2019/1/1

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KW - Huntingtin-associated protein-1 (HAP1)

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