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

, : Abeta promotes Alzheimer's disease-like cytoskeleton abnormalities with consequences to APP processing in neurons. Journal of Neurochemistry 113(3): 761-771

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


PMID: 20345756

DOI: 10.1111/j.1471-4159.2010.06643.x

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