Plant sterols the better cholesterol in Alzheimer's disease? A mechanistical study.
Plant sterols the better cholesterol in Alzheimer's disease? A mechanistical study.
Alzheimer’s disease is the most prevalent progressive neurodegenerative disorder, pathologically characterized by the extracellular deposition of small protein fragments (Ab peptides) in the brain. These Ab peptides are released by sequential cleavage of a larger protein, the Alzheimer amyloid precursor protein (APP). The Ab generating cleavage of APP requires the proteolytic activity of two enzymes, b- and g-secretase. APP and the enzymes are integral components of the cellular membrane. Such membranes consist of cellular derived lipids and lipids of dietary origin, discussed to influence the production of Ab peptides and the risk for AD in general. Cholesterol has already been shown to increase Ab production, however, the effect of phytosterols, the molecular equivalents of cholesterol in plants, on Ab generation is unknown. We investigated the effect of the most prevalent dietary plant sterols – stigmasterol, b-sitosterol, brassicasterol, campesterol – in comparison to cholesterol on Ab generation. Here we report that plant sterols have lower Ab inducing potency than cholesterol up to the point of partial inhibition of Ab generation, indicating that certain plant sterols might be useful bioactive food compounds to reduce Ab generation and the risk for AD.
High levels of cholesterol have been long associated with the pathogenesis of AD. Cholesterol is highly enriched in specialized microdomains of the membrane, also called lipid rafts, which have been implicated in Ab generating (amyloidogenic) processing of APP. Plant sterols have a structure very similar to that of cholesterol and are also organized in lipid rafts within plant cell membranes and might therefore interfere with cholesterol-dependent cellular processes in the brain, including the molecular mechanisms involved in AD.
In order to investigate the effect of plant sterols on the proteolytic processing of APP, we determined the APP cleavage products Ab (implicated in the generation of AD) and sAPPa (an alternative, non-amyloidogenic product, that is considered to be protective for AD generated by the a-secretase). Furthermore we analyzed the direct effect of plant sterols on b-, g- and a-secretase activities as well as their impact on gene expression and protein level of these enzymes. Moreover, because the lipid rafts are involved in b- and g-secretase cleavage of APP and alterations in the cholesterol level have been shown to influence Ab generation, we analyzed whether plant sterols affect cholesterol distribution and thus g-secretase activity in lipid raft membrane microdomains.
The analysis of the molecular details showed that a combination of mechanisms is involved in sterol mediated regulation of Ab production. E.g. cholesterol directly increases b- and g-secretase activity, significantly elevated gene expression of all g-secretase components and of b-secretase BACE1, attended by an increase of PS1 and BACE1 protein level. Additionally, it decreases the amount of the alternative, non-amyloidogenic product sAPPa and the activity of the enzymes leading towards this pathway. Cholesterol therefore increases Ab generation by directly activating b- and g-secretase enzyme activity and by elevating gene expression of b- and g-secretase and downregulation of the alternative pathway. For b-sitosterol we observed a nearly identical increase in b- and g-secretase activity resulting in significantly increased Ab levels. In contrast to cholesterol b-sitosterol only elevates BACE1 gene expression whereas gene expression of the g-secretase components is not affected. In sharp contrast to cholesterol, b-sitosterol also increased the alternative, non-amyloidogenic pathway.
Stigmasterol was the only plant sterol which significantly decreased Ab levels. Stigmasterol directly inhibits b-secretase activity but not the activity of g-secretase isolated from cellular membranes. Although the specific activity of the g-secretase (turnover rate per molecule enzyme) is unchanged, the absolute protein level of g-secretase is reduced due to decreased gene expression of all g-secretase components. Moreover, stigmasterol incorporates in lipid raft membrane microdomains and displaces the g-secretase activity enhancer cholesterol out of lipid rafts. Together these effects amount to a considerable inhibition of the cells capability to produce Ab.
Despite their close structural similarities to cholesterol, all plant sterols had a lower capacity to increase Ab production compared to cholesterol. Also in vivo, b- and g-secretase activities were significantly decreased in mice fed with a stigmasterol-enriched diet, accompanied by reduced Ab levels in the brain, emphasizing that dietary intake of stigmasterol might be useful to lower the risk for AD. However, although food products containing plant sterols have been widely used as a functional food to reduce the risk for coronary heart disease and might be beneficial in AD prevention, one has to taken into consideration that plant sterols naturally occur in the diet as intermixture and might not only interfere with critical processes in AD but also with further cholesterol-dependent functions in the cell.
The results of our study show that plant sterols are bioactive food compounds having functional consequences in the brain and are involved in critical processes of AD pathogenesis