Alzheimer disease is characterized by accumulation of the ␤-amyloid peptide (A␤) generated by ␤-and ␥-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing ␤-and ␥-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of ␣-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in ␥-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing A␤ release. DHA has a typical pleiotropic effect; DHA-mediated A␤ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects.

a b s t r a c tHeat stress is a common and, therefore, an important environmental impact on cells and organisms. While much attention has been paid to severe heat stress, moderate temperature elevations are also important. Here we discuss temperature sensing and how responses to heat stress are not necessarily dependent on denatured proteins. Indeed, it is clear that membrane lipids have a pivotal function. Details of membrane lipid changes and the associated production of signalling metabolites are described and suggestions made as to how the interconnected signalling network could be modified for helpful intervention in disease.