Date Published: March 1, 2018
Publisher: Elsevier, Inc
Author(s): Katherine J. Sellers, Christina Elliott, Joshua Jackson, Anshua Ghosh, Elena Ribe, Ana I. Rojo, Heledd H. Jarosz-Griffiths, Iain A. Watson, Weiming Xia, Mikhail Semenov, Peter Morin, Nigel M. Hooper, Rod Porter, Jane Preston, Raya Al-Shawi, George Baillie, Simon Lovestone, Antonio Cuadrado, Michael Harte, Paul Simons, Deepak P. Srivastava, Richard Killick.
•Aβ synaptotoxicity is Dickkopf-1 and Wnt-PCP dependent.•The Wnt-PCP pathway drives Aβ-driven synapse loss via RhoA and ROCK.•ROCK inhibitor fasudil blocks Aβ-driven synapse loss and cognitive impairment.•Fasudil should be assessed for repurposing for Alzheimer’s disease.
Amyloid β (Aβ) has long been associated with Alzheimer’s disease (AD) through a propensity to form insoluble deposits, senile plaques, a hallmark of the AD brain. Overwhelming genetic and experimental evidence indicates that Aβ and its parent molecule, the Aβ precursor protein (APP), are key players in the neuropathogenic processes driving AD. Aβ readily self-associates to form a range of soluble oligomers and insoluble fibers, and the current consensus view holds that it is the small soluble oligomeric forms of Aβ rather than the plaques themselves that are the neurotoxic species , , . We have previously found that Aβ-driven increases in tau phosphorylation (a second hallmark of the disease) and neuronal death are dependent on activation of a branch of Wingless/Wnt signaling known as the Wnt–planar cell polarity (Wnt-PCP) pathway, specifically the arm of Wnt-PCP acting through Jun N-terminal kinase (JNK) and its target, c-Jun, to regulate gene transcription  (please see glossary for definitions of these and other terms that occur below). We have shown that Aβ activates Wnt-PCP through the ability of Aβ to induce Dickkopf-1 (Dkk1). Dkk1 then blocks the binding interaction between LRP6 and frizzled, preventing canonical Wnt-β-catenin activity and concomitantly activating Wnt-PCP signaling , . Furthermore, our data indicate that Dkk1 and Wnt-PCP not only shape the transcriptomic profile of the AD brain but also the activity of pathways within the brain most closely associated with the AD process , . The top four most significant of these pathways are the adherens junction, Wnt signaling, TGF-β signaling, and long-term potentiation, all of which are intimately involved in synaptic plasticity , , .
Opposing roles for the canonical and noncanonical Wnt-signaling pathways in synapse homeostasis have been previously recognized, with canonical Wnt-promoting synapse formation and stabilization  and noncanonical Wnt-promoting synapse disassembly/pruning , . Under normal physiological conditions, both pathways likely act in a highly regulated and coordinated manner to achieve appropriate levels of synaptic plasticity and normal cognitive functioning. Abnormal levels of Aβ result in cognitive impairment and memory deficits by disrupting these processes.