Endolysosome Mechanisms Associated with Alzheimer's Disease-like Pathology in Rabbits Ingesting Cholesterol-Enriched Diet

Abstract

Alzheimer's disease (AD) is characterized clinically by progressive disturbances in memory, judgment, reasoning, and olfaction, and pathologically by loss of synaptic integrity, extracellular accumulations of amyloid-β (Aβ) containing plaques, and intraneuronal tangles composed of hyperphosphorylated tau. Endolysosome dysfunction is one of the earliest pathological features of AD and cholesterol, a known risk factor for sporadic AD, is up-taken into neurons via receptor-mediated endocytosis. Accordingly, we determined the extent to which endolysosome dysfunction is associated with pathological features observed in rabbits fed cholesterol-enriched diet; a well-characterized model of sporadic AD. Olfactory bulbs were taken from rabbits fed for 12 weeks a diet enriched with 2% cholesterol and endolysosome morphology and function as well as AD-like pathology were investigated using enzyme activity measurements, immunoblotting and immunostaining techniques. In olfactory bulbs of rabbits fed cholesterol-enriched diet, we observed enlarged endolysosomes containing increased accumulations of ApoB containing cholesterol and increased accumulations of synaptophysin, Aβ, and phosphorylated tau. The cholesterol-enriched diet also significantly decreased specific enzyme activities of the endolysosome enzymes acid phosphatase and cathepsin D. Decreased synaptic area was present in olfactory bulbs of cholesterol-fed rabbits as indicated by significant decreases in protein expression levels of the synaptic area marker protein synaptophysin. Our results suggest strongly that elevated circulating cholesterol plays an important role in the pathogenesis of AD, and that alterations in endolysosome structure and function are associated with cholesterol diet-induced AD-like pathology.