Tau Peptide (306-317)

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common causes of dementia and movement disorders in the elderly. While progressive accumulation of oligomeric amyloid-beta protein (Abeta) has been identified as one of the central toxic events in AD leading to synaptic dysfunction, accumulation of alpha-synuclein (alpha-syn) resulting in the formation of oligomers has been linked to PD. Most of the studies in AD have been focused on investigating the role of Abeta and Tau; however, recent studies suggest that alpha-syn might also play a role in the pathogenesis of AD. For example, fragments of alpha-syn can associate with amyloid plaques and Abeta promotes the aggregation of alpha-syn in vivo and worsens the deficits in alpha-syn tg mice. Moreover, alpha-syn has also been shown to accumulate in limbic regions in AD, Down's syndrome, and familial AD cases. Abeta and alpha-syn might directly interact under pathological conditions leading to the formation of toxic oligomers and nanopores that increase intracellular calcium. The interactions between Abeta and alpha-syn might also result in oxidative stress, lysosomal leakage, and mitochondrial dysfunction. Thus, better understanding the steps involved in the process of Abeta and alpha-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the accumulation of toxic proteins in AD.

Introduction: Synapse 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. Methods: We 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. Results: We 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. Discussion: 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.