Aβ promotes Alzheimer's disease-like cytoskeleton abnormalities with consequences to APP processing in neurons

P>A beta is proteolytically produced from the Alzheimer's amyloid precursor protein (APP). Major properties attributed to A beta include neurotoxic effects that contribute to Alzheimer's disease neurodegeneration. However, A beta can also affect APP processing and trafficking that, in neurons, is anterogradelly transported via microtubules in a kinesin-associated manner. Herein we show that A beta can induce accumulation of intracellular sAPP in primary neuronal cultures. Subcellular fractionation studies and immunofluorescence analysis revealed that upon A beta exposure sAPP retention was localized to cytoskeleton associated vesicular structures along the neurite processes, positive for an APP N-terminal antibody and negative for an APP C-terminal antibody. These vesicular structures were also positive for kinesin light chain 1 (KLC). We confirm that A beta alters both actin and microtubule networks. It increases F-actin polymerization and we report for the first time that A beta decreases alpha-tubulin acetylation. The use of cytoskeleton associated drugs partially reversed the A beta-induced effects on sAPP secretion. The data here presented show that A beta causes intracellular sAPP retention by inducing alterations in the cytoskeleton network, thus contributing to impaired APP/sAPP vesicular transport. Moreover, the data strengthens the hypothesis that A beta-induces neurodegeneration and provides a potential mechanism of action, as impaired vesicular and axonal transport have been linked to Alzheimer's disease pathology.