Caffeine protects against oxidative stress and Alzheimer's disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet.
Cholesterol has been linked to the pathogenesis of sporadic Alzheimer's disease (AD) as a risk factor increasing beta-amyloid (Abeta) and oxidative stress levels. Caffeine has antioxidant properties and has been demonstrated to reduce Abeta levels in transgenic mouse models of familial AD. However, the effects of caffeine on cholesterol-induced sporadic AD pathology have not been determined. In this study, we determined the effects of caffeine on Abeta levels, tau phosphorylation, oxidative stress generation, and caffeine-target receptors in rabbits fed a 2% cholesterol-enriched diet, a model system for sporadic AD. Our results showed that the cholesterol-enriched diet increased levels of Abeta, tau phosphorylation, and oxidative stress measured as increased levels of reactive oxygen species and isoprostanes, glutathione depletion, and increased levels of endoplasmic reticulum stress marker proteins. Additionally, the cholesterol-enriched diet reduced the levels of adenosine A(1) receptors (A(1)R) but not ryanodine or adenosine A(2A) receptors. Caffeine, administered at 0.5 and 30mg/day in the drinking water, reduced the cholesterol-induced increase in Abeta, phosphorylated tau, and oxidative stress levels and reversed the cholesterol-induced decrease in A(1)R levels. Our results suggest that even very low doses of caffeine might protect against sporadic AD-like pathology.
Prasanthi
Jaya R P
JR
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202, USA.
Dasari
Bhanu
B
Marwarha
Gurdeep
G
Larson
Tyler
T
Chen
Xuesong
X
Geiger
Jonathan D
JD
Ghribi
Othman
O
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000682:Amyloid / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000096:biosynthesis / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism
D000682:Amyloid; D002791:Cholesterol, Dietary; D017382:Reactive Oxygen Species; D043682:Receptor, Adenosine A1; D016875:tau Proteins; D002110:Caffeine