Membrane-Associated Effects of Glucocorticoid on BACE1 Upregulation and Aβ Generation: Involvement of Lipid Raft-Mediated CREB Activation

Increased generation of amyloid β peptide (Aβ) derived from amyloid precursor protein (APP) is the primary pathological characteristic of Alzheimer’s disease (AD). However, the sub cellular compartment in which APP undergoes cleavage by secretases to generate Aβ is not precisely known. Compelling evidences suggest that amyloidogenic processing of APP occurs in lipid rafts. An indirect support for lipid raft processing of APP includes the localization of Aβ, APP C-terminal fragments (CTFs), APP holoprotein and secretases in the lipid raft microdomains, although few studies failed to find APP in the lipid rafts. The indirect support also comes from both experimental and clinical studies involving modulation of cholesterol levels and its effect on Aβ generation. Moderate depletion of cholesterol results in significant reduction in Aβ levels and increased dietary intake of cholesterol leads to higher levels of Aβ production suggesting that amyloidogenic processing of APP strongly depends on cholesterol levels and therefore on lipid raft integrity. More convincing evidence that lipid rafts are critical for amyloidogenic processing of APP comes from studies using antibody-mediated co-patching of APP and BACE1 which results in lipid raft association of APP and BACE1 and increased Aβ generation. Further, an endosome/lipid raft targeting of β-secretase inhibitor by sterol-mediated anchoring leading to reduced Aβ generation also suggests that lipid rafts are pivotal for amyloidogenic processing of APP. In the absence of an effective therapy for AD, proteins responsible for delivery of APP to lipid rafts including LRP, RanBP9 and ApoER2 may be excellent therapeutic targets in AD.

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APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation

Stem Cell Reports ◽

10.1016/j.stemcr.2021.07.017 ◽

2021 ◽

Vol 16 (9) ◽

pp. 2128-2137

Author(s):

Se-In Lee ◽

Woojin Jeong ◽

Heejin Lim ◽

Sukhee Cho ◽

Hyein Lee ◽

...

Keyword(s):

Lipid Raft ◽

Human Astrocytes ◽

Aβ Generation

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Preferred Endocytosis of Amyloid Precursor Protein from Cholesterol-Enriched Lipid Raft Microdomains

Molecules ◽

10.3390/molecules25235490 ◽

2020 ◽

Vol 25 (23) ◽

pp. 5490

Author(s):

Yoon Young Cho ◽

Oh-Hoon Kwon ◽

Sungkwon Chung

Keyword(s):

Amyloid Precursor Protein ◽

Lipid Rafts ◽

Lipid Raft ◽

Amyloid Β ◽

Precursor Protein ◽

Cholesterol Levels ◽

Elevated Cholesterol ◽

Aβ Generation ◽

Lipid Raft Microdomains ◽

First Time

Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis and delivered to endo/lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to nonraft-localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results demonstrate for the first time that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease.

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Preferred endocytosis of amyloid precursor protein from cholesterol-enriched lipid raft microdomains

10.1101/2020.06.26.172874 ◽

2020 ◽

Author(s):

Yoon Young Cho ◽

Oh-Hoon Kwon ◽

Sungkwon Chung

Keyword(s):

Amyloid Precursor Protein ◽

Lipid Rafts ◽

Lipid Raft ◽

Therapeutic Strategy ◽

Amyloid Β ◽

Precursor Protein ◽

Cholesterol Levels ◽

Elevated Cholesterol ◽

Aβ Generation ◽

Lipid Raft Microdomains

AbstractAmyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis, and delivered to endosomes and lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to non-raft localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results indicate that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease.

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