ALZHEIMER’S DISEASE, CHOLESTEROL & AMYLOID b: DOGMA PREVAILS
Up to now, cholesterols’ role in Alzheimer's disease was mainly explained in terms of the dogmatic view that a reduction of amyloid burden by lowering cholesterol is beneficial [5, fr8], fr9, fr10]. This viewpoint (that become questioned in October 2002 Neurology article by Fassbender et al. [fr9]). was based on the in vitro data on the importance of cholesterol in amyloid precursor protein processing and Ab generation [4, 5]. Two recent articles further showed that cellular generation of Ab is modulated by cholesterol compartmentation and intracellular cholesteryl-ester levels [fr8].
The biochemical relation of cholesterol and Ab, however, is bidirectional (See Ref.4 for detailed bibliography).
Moreover, the modulation of neuronal cholesterol dynamics by Ab may have important functional consequences.
Particularly, Ab modulates neuronal cholesterol esterification, influx, efflux, and thus may regulate neural cholesterol intracellular compartmentation and extracellular trafficking . Ab also modulates neuronal physical property of membrane fluidity important for receptor function, and it is well possible that this effect is mediated by the peptide antioxidant properties (see next section). Additionally, Ab increases neural lipid synthesis, in contrast to the peptide inhibitory effect, observed in human hepatic HepG2 and in HEK293 cells, in fetal rat liver and in neuronal tissue under the condition of potassium-evoked depolarization and under oxidative stress. The latter results highlight the importance of developmental, tissue and neuronal functional specificity of Ab-cholesterol biochemical relation, which may vary in different brain regions and be of special importance in determining Alzheimer's specific areas of neurodegeneration. The latter data also suggest that Ab may serve a molecular messanger function and manage the crosstalk of hepatic, systemic and brain cholesterol, and thus maintain the tissue-specific coordinate regulation of cholesterol biosynthesis. Taken together, the above functional consideration and recent data on the importance of cholesterol compartmentation for Ab generation indicate feedback mechanism between cholesterol and Ab homeostasis, additionally supported by a dependency of amyloid precursor protein processing and Ab production on the site 2 processing of SREBP and associated inability of cells to upregulate the expression of several enzymes and proteins involved in cholesterol synthesis and turnover .