Plant Sterols the Better Cholesterol in Alzheimer's Disease? A Mechanistical Study

Abstract

Amyloid-␤ (A␤), major constituent of senile plaques in Alzheimer's disease (AD), is generated by proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretase. Several lipids, especially cholesterol, are associated with AD. Phytosterols are naturally occurring cholesterol plant equivalents, recently been shown to cross the blood-brain-barrier accumulating in brain. Here, we investigated the effect of the most nutritional prevalent phytosterols and cholesterol on APP processing. In general, phytosterols are less amyloidogenic than cholesterol. However, only one phytosterol, stigmasterol, reduced A␤ generation by (1) directly decreasing ␤-secretase activity, (2) reducing expression of all ␥-secretase components, (3) reducing cholesterol and presenilin distribution in lipid rafts implicated in amyloidogenic APP cleavage, and by (4) decreasing BACE1 internalization to endosomal compartments, involved in APP ␤-secretase cleavage. Mice fed with stigmasterol-enriched diets confirmed protective effects in vivo, suggesting that dietary intake of phytosterol blends mainly containing stigmasterol might be beneficial in preventing AD.

Cyclopamine Modulates γ-Secretase-mediated Cleavage of Amyloid Precursor Protein by Altering Its Subcellular Trafficking and Lysosomal Degradation

“…In fact, stigmasterol demonstrated anti-amyloidogenic properties, decreased ␤-secretase cleavage of APP, and decreased A␤ generation. Moreover, mice fed stigmasterol-enriched diets showed decreased ␥-secretase complex protein expression but lacked direct inhibition of ␥-secretase activity in isolated mouse brain tissue (32). We also observed that cyclopamine treatment decreases ␥-secretase-mediated proteolysis of APP without inhibiting ␥-secretase activity directly.…”

“…Phytosterols were recently shown to modify APP metabolism. Some phytosterols increased amyloidogenic processing and A␤ levels, and others decreased A␤ levels (32). In fact, stigmasterol demonstrated anti-amyloidogenic properties, decreased ␤-secretase cleavage of APP, and decreased A␤ generation.…”

Oxidized Docosahexaenoic Acid Species and Lipid Peroxidation Products Increase Amyloidogenic Amyloid Precursor Protein Processing

“…Beside the fact that APP itself and its processing secretases are all transmembrane proteins, amyloidogenic APP processing is discussed to be dependent on particular membrane microdomains, called lipid rafts, enriched in cholesterol and sphingolipids [5]. Furthermore, several lipids have been shown to alter Aβ generation, including gangliosides, sphingomyelin, trans -fatty acids, phytosterols, cholesterol and docosahexaenoic acid (DHA) [6,7,8,9,10,11,12]. DHA, an ω-3 polyunsaturated fatty acid (PUFA) predominantly found in marine fish and algae, was shown to reduce Aβ production in vitro and in animal models of AD [12,13,14,15].…”

Caffeine with Links to NAFLD and Accelerated Brain Aging

“…Phytosterols should be consumed (1-2 g/day) and excessive intake of phytosterols leads to neurotoxicity with neurodegeneration [37]. Phytosterols cross the blood-brain barrier in neurons to maintain neuron amyloid beta homeostasis [161]. Consumption of plant-based foods essential for phytosterol ingestion should be assessed for caffeine content since approximately 40 caffeine containing plants have been reported.…”