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

Abstract

J. Neurochem. (2010) 113, 761–771. Abstract 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.

Actin dynamics shape microglia effector functions

“…The actin cytoskeleton is sensitive to oxidative stress, which may lead to oxidation of exposed cysteine residues, disulphide bonds and, ultimately, reduced dynamic cytoskeletal plasticity (Bencsath et al 1996;Dalle-Donne et al 2001;Haarer and Amberg 2004). Furthermore, both Ab and tau have been demonstrated to promote actin polymerization (Fulga et al 2007;Henriques et al 2010;Frandemiche et al 2014). The results gathered here, therefore, have a direct bearing on our understanding of the role of impaired actin dynamics in age-dependent neurodegeneration and Alzheimer's pathogenesis.…”

“…Abnormal bundling and accumulation of filamentous actin have also been implicated in the etiopathogenesis of adult-onset neurodegenerative conditions such as Huntington's disease, stroke, severe epileptic seizures, and most notably, Alzheimer's dementia. Both amyloid-b and phosphorylated tau protein promote actin stabilization (Furukawa et al 1997;Endres et al 1999;Fulga et al 2007;Henriques et al 2010;Kwan et al 2012).…”

Axonal Transport Defects in Alzheimer’s Disease

“…Through the first pathway, Aβ decreases a-tubulin acetylation, which then decreases microtubule stability. The level of acetylated a-tubulin is decreased [32] as the level of histone deacetylase 6 (HDAC6) [33], which can deacetylate α-tubulin, is increased in the AD patients' brains. Inhibiting HDAC6 significantly restores the velocity and motility of the mitochondria in both anterograde and retrograde ATs.…”

Abeta(1-42) induces abnormal alternative splicing of tau exons 2/3 in NGF-induced PC12 cells

“…Morphologically, reports of Aβ effects on neuronal cells have included the formation of autophagic vacuoles, intracellular aggregates of Aβ (Pajak et al 2009), and cytoskeleton alterations by accumulation of soluble amyloid-β precursor protein (sAβPP) (Henriques et al 2010). Neurite retraction in PC12 cells has been associated with the inhibition of tau expression (Hanemaaijer and Ginzburg 1991) and phosphorylation during programmed cell death (Nuydens et al 1997).…”