Abstract

Alpha-synuclein is a small soluble, cytosolic protein which associates with vesicular membranes. It is a component of intracellular Lewy bodies present in Parkinson's disease and a subset of Alzheimer's disease (AD). In addition, early studies identified a fragment of alpha-synuclein in the amyloid plaques of AD patients. Hypothesizing that alpha-synuclein might modify the AD pathogenic process, we crossed the Tg2576 strain of APP transgenic mice onto an alpha-synuclein knockout background to determine the effects of alpha-synuclein on Abeta production and plaque deposition. We found that alpha-synuclein deficiency does not affect the Abeta levels, nor does it alter the age of onset of plaque pathology. To our surprise, however, loss of alpha-synuclein leads to a significant increase in plaque load in all areas of the forebrain at 18 months of age. This is associated with an increase in another synaptic protein, synaptophysin. We thus conclude that alpha-synuclein is not involved in seeding of the plaques, but rather suppresses the progression of plaque pathology at advanced stages.