Abstract
IntroductionSynapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt–planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death. MethodsWe compared the effects of Aβ and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway. ResultsWe demonstrate that Aβ synaptotoxicity is also Dkk1 and Wnt-PCP dependent, mediated by the arm of Wnt-PCP regulating actin cytoskeletal dynamics via Daam1, RhoA and ROCK, and can be blocked by the drug fasudil. DiscussionOur data add to the importance of aberrant Wnt signaling in Alzheimer's disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease.
Highlights
Amyloid b (Ab) has long been associated with Alzheimer’s disease (AD) through a propensity to form insoluble deposits, senile plaques, a hallmark of the AD brain
Our data add to the importance of aberrant Wnt signaling in Alzheimer’s disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease
We extend these observations by showing that increases in both Dkk1 mRNA and protein are readily detectable in cultured rodent neurons following treatment with the active portion of Ab, Ab25–35, and by soluble Ab1–42 oligomers (AbO) within 2–3 hours and within 4 hours by AbO at nanomolar concentrations (Fig. 1A and 1B)
Summary
Amyloid b (Ab) 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. K.J. Sellers et al / Alzheimer’s & Dementia 14 (2018) 306–317 soluble oligomers and insoluble fibers, and the current consensus view holds that it is the small soluble oligomeric forms of Ab rather than the plaques themselves that are the neurotoxic species [1,2,3].
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