Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase

Abstract

The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.

Cellular levels of growth factor receptor bound protein 2 (Grb2) and cytoskeleton stability are correlated in a neurodegenerative scenario

“…4B(iv),C]. Interestingly, both ROCK isoforms and PAK1, an activator of LIMK1 by phosphorylation (Cuberos et al, 2015; Mendoza-Naranjo et al, 2012), expectedly reduced LIMK1 activity under condition A 1.28 fold ( n =4) and activated it significantly under condition B 1.335-fold ( n =4) [Fig. 4B(v),C].…”

Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

“…siRNA knockdown of cofilin abolished both A␤ and RanBP9-induced apoptosis (122). In hippocampal neurons, fibrillar A␤ was able to alter the PAK1/LIMK1/cofilin axis and thereby actin organization (123).…”

The Amyloidogenic Pathway Meets the Reelin Signaling Cascade: A Cytoskeleton Bridge Between Neurodevelopment and Neurodegeneration

“…Consistently, hippocampal neurons treated with fibrillar Aβ show increased activity of PAK and its downstream substrate LIMK1 [93][94], most likely through a Rac1 and Cdc42 dependent mechanism [95]. Moreover, the treatment with oligomers of Aβ 1-40 has the opposite effect, decreasing the phosphorylation of PAK, indicating that oligomeric forms may be responsible for the overall reduction in PAK phosphorylation [92].…”

“…In example, actin-rods occur in a subpopulation of neurons in organotypic slices treated with Aβ [96]. (Figure 1B) The mechanisms involved in the Aβ-mediated cofilin dephosphorylation are dependent on changes in the activity of its upstream kinase, LIMK [90], and the activity of two known cofilin phosphatases, chronophin [97] and slingshot [94].…”