Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation

Shanshan Li, Nicholas H. Geiger, Mahmoud L. Soliman, Liang Hui, Jonathan D. Geiger, Xuesong Chen

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Intraneuronal accumulation and extracellular deposition of amyloid-β (Aβ) protein continues to be implicated in the pathogenesis of Alzheimer's disease (AD), be it familial in origin or sporadic in nature. Aβ is generated intracellularly following endocytosis of amyloid-β protein precursor (AβPP), and, consequently, factors that suppressAβPP internalization may decrease amyloidogenic processing ofAβPP. Here we tested the hypothesis that caffeine decreasesAβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosineA3 receptor (A3R) antagonist as well as siRNAknockdown ofA3Rs mimicked the effects of caffeine on neuronal internalization of LDL cholesterol. Further implicating A3Rs were findings that a specific A3R agonist increased neuronal internalization of LDL cholesterol. In addition, caffeine as well as siRNA knockdown of A3Rs blocked the ability of LDL cholesterol to increase Aβ levels. Furthermore, caffeine blocked LDL cholesterol-induced decreases inAβPP protein levels in neuronal plasma membranes, increased surface expression ofAβPP on neurons, and theA3R antagonist as well as siRNA knockdown of A3Rs mimicked the effects of caffeine on AβPP surface expression. Moreover, the A3R agonist decreased neuronal surface expression ofAβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A3R-mediated internalization of AβPP.

Original languageEnglish (US)
Pages (from-to)73-83
Number of pages11
JournalJournal of Alzheimer's Disease
Volume47
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Adenosine A3 Receptors
Amyloid beta-Protein Precursor
Caffeine
Amyloid
LDL Cholesterol
Small Interfering RNA
Neurons
Serum Amyloid A Protein
Lipoprotein(a)
Aptitude
Endocytosis
Alzheimer Disease
Cell Membrane

Keywords

  • Adenosine A receptor
  • Alzheimer's disease
  • Amyloid-β
  • Amyloid-β protein precursor
  • Caffeine
  • Endocytosis
  • LDL cholesterol

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation. / Li, Shanshan; Geiger, Nicholas H.; Soliman, Mahmoud L.; Hui, Liang; Geiger, Jonathan D.; Chen, Xuesong.

In: Journal of Alzheimer's Disease, Vol. 47, No. 1, 01.01.2015, p. 73-83.

Research output: Contribution to journalArticle

Li, Shanshan ; Geiger, Nicholas H. ; Soliman, Mahmoud L. ; Hui, Liang ; Geiger, Jonathan D. ; Chen, Xuesong. / Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation. In: Journal of Alzheimer's Disease. 2015 ; Vol. 47, No. 1. pp. 73-83.
@article{a8d3c9a622624e9888b002d9258db707,
title = "Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation",
abstract = "Intraneuronal accumulation and extracellular deposition of amyloid-β (Aβ) protein continues to be implicated in the pathogenesis of Alzheimer's disease (AD), be it familial in origin or sporadic in nature. Aβ is generated intracellularly following endocytosis of amyloid-β protein precursor (AβPP), and, consequently, factors that suppressAβPP internalization may decrease amyloidogenic processing ofAβPP. Here we tested the hypothesis that caffeine decreasesAβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosineA3 receptor (A3R) antagonist as well as siRNAknockdown ofA3Rs mimicked the effects of caffeine on neuronal internalization of LDL cholesterol. Further implicating A3Rs were findings that a specific A3R agonist increased neuronal internalization of LDL cholesterol. In addition, caffeine as well as siRNA knockdown of A3Rs blocked the ability of LDL cholesterol to increase Aβ levels. Furthermore, caffeine blocked LDL cholesterol-induced decreases inAβPP protein levels in neuronal plasma membranes, increased surface expression ofAβPP on neurons, and theA3R antagonist as well as siRNA knockdown of A3Rs mimicked the effects of caffeine on AβPP surface expression. Moreover, the A3R agonist decreased neuronal surface expression ofAβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A3R-mediated internalization of AβPP.",
keywords = "Adenosine A receptor, Alzheimer's disease, Amyloid-β, Amyloid-β protein precursor, Caffeine, Endocytosis, LDL cholesterol",
author = "Shanshan Li and Geiger, {Nicholas H.} and Soliman, {Mahmoud L.} and Liang Hui and Geiger, {Jonathan D.} and Xuesong Chen",
year = "2015",
month = "1",
day = "1",
doi = "10.3233/JAD-142223",
language = "English (US)",
volume = "47",
pages = "73--83",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "1",

}

TY - JOUR

T1 - Caffeine, Through Adenosine A3 Receptor-Mediated Actions, Suppresses Amyloid-β Protein Precursor Internalization and Amyloid-β Generation

AU - Li, Shanshan

AU - Geiger, Nicholas H.

AU - Soliman, Mahmoud L.

AU - Hui, Liang

AU - Geiger, Jonathan D.

AU - Chen, Xuesong

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Intraneuronal accumulation and extracellular deposition of amyloid-β (Aβ) protein continues to be implicated in the pathogenesis of Alzheimer's disease (AD), be it familial in origin or sporadic in nature. Aβ is generated intracellularly following endocytosis of amyloid-β protein precursor (AβPP), and, consequently, factors that suppressAβPP internalization may decrease amyloidogenic processing ofAβPP. Here we tested the hypothesis that caffeine decreasesAβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosineA3 receptor (A3R) antagonist as well as siRNAknockdown ofA3Rs mimicked the effects of caffeine on neuronal internalization of LDL cholesterol. Further implicating A3Rs were findings that a specific A3R agonist increased neuronal internalization of LDL cholesterol. In addition, caffeine as well as siRNA knockdown of A3Rs blocked the ability of LDL cholesterol to increase Aβ levels. Furthermore, caffeine blocked LDL cholesterol-induced decreases inAβPP protein levels in neuronal plasma membranes, increased surface expression ofAβPP on neurons, and theA3R antagonist as well as siRNA knockdown of A3Rs mimicked the effects of caffeine on AβPP surface expression. Moreover, the A3R agonist decreased neuronal surface expression ofAβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A3R-mediated internalization of AβPP.

AB - Intraneuronal accumulation and extracellular deposition of amyloid-β (Aβ) protein continues to be implicated in the pathogenesis of Alzheimer's disease (AD), be it familial in origin or sporadic in nature. Aβ is generated intracellularly following endocytosis of amyloid-β protein precursor (AβPP), and, consequently, factors that suppressAβPP internalization may decrease amyloidogenic processing ofAβPP. Here we tested the hypothesis that caffeine decreasesAβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosineA3 receptor (A3R) antagonist as well as siRNAknockdown ofA3Rs mimicked the effects of caffeine on neuronal internalization of LDL cholesterol. Further implicating A3Rs were findings that a specific A3R agonist increased neuronal internalization of LDL cholesterol. In addition, caffeine as well as siRNA knockdown of A3Rs blocked the ability of LDL cholesterol to increase Aβ levels. Furthermore, caffeine blocked LDL cholesterol-induced decreases inAβPP protein levels in neuronal plasma membranes, increased surface expression ofAβPP on neurons, and theA3R antagonist as well as siRNA knockdown of A3Rs mimicked the effects of caffeine on AβPP surface expression. Moreover, the A3R agonist decreased neuronal surface expression ofAβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A3R-mediated internalization of AβPP.

KW - Adenosine A receptor

KW - Alzheimer's disease

KW - Amyloid-β

KW - Amyloid-β protein precursor

KW - Caffeine

KW - Endocytosis

KW - LDL cholesterol

UR - http://www.scopus.com/inward/record.url?scp=84940952020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940952020&partnerID=8YFLogxK

U2 - 10.3233/JAD-142223

DO - 10.3233/JAD-142223

M3 - Article

C2 - 26402756

AN - SCOPUS:84940952020

VL - 47

SP - 73

EP - 83

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 1

ER -