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


Address correspondence and reprint requests to Odete A. B. da Cruz e Silva, Centro de Biologia Celular, Secção Autónoma de Ciências da Saúde, Universidade de Aveiro, 3810-193 Aveiro, Portugal. E-mail: odetecs@ua.pt


J. Neurochem. (2010) 113, 761–771.


Aβ is proteolytically produced from the Alzheimer’s amyloid precursor protein (APP). Major properties attributed to Aβ include neurotoxic effects that contribute to Alzheimer’s disease neurodegeneration. However, Aβ can also affect APP processing and trafficking that, in neurons, is anterogradelly transported via microtubules in a kinesin-associated manner. Herein we show that Aβ can induce accumulation of intracellular sAPP in primary neuronal cultures. Subcellular fractionation studies and immunofluorescence analysis revealed that upon Aβ 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 Aβ alters both actin and microtubule networks. It increases F-actin polymerization and we report for the first time that Aβ decreases α-tubulin acetylation. The use of cytoskeleton associated drugs partially reversed the Aβ-induced effects on sAPP secretion. The data here presented show that Aβ 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 Aβ-induces neurodegeneration and provides a potential mechanism of action, as impaired vesicular and axonal transport have been linked to Alzheimer’s disease pathology.