Pre-plaque conformational changes in Alzheimer's disease-linked Aβ and APP

Reducing levels of the aggregation-prone A beta peptide that accumulates in the brain with Alzheimer's disease (AD) has been a major target of experimental therapies. An alternative approach may be to stabilize the physiological conformation of A beta. To date, the physiological state of A beta in brain remains unclear, since the available methods used to process brain tissue for determination of A beta aggregate conformation can in themselves alter the structure and/or composition of the aggregates. Here, using synchrotron-based Fourier transform infrared micro-spectroscopy, non-denaturing gel electrophoresis and conformational specific antibodies we show that the physiological conformations of A beta and amyloid precursor protein (APP) in brain of transgenic mouse models of AD are altered before formation of amyloid plaques. Furthermore, focal A beta aggregates in brain that precede amyloid plaque formation localize to synaptic terminals. These changes in the states of A beta and APP that occur prior to plaque formation may provide novel targets for AD therapy.