Role of the Slingshot-1 pathway in APP and Tau pathogenesis

Kang, David

Abstract

The major defining pathological hallmarks of Alzheimer?s disease (AD) are the accumulations of amyloid ? (A?) and hyperphosphorylated Tau, associated with neuroinflammation, mitochondrial dysfunction, cytoskeletal aberrations, and synaptic loss. Multiple studies have shown that A?-induced neurotoxic signals require Tau, since the loss of Tau abrogates many deleterious effects of A?. Despite the clear pathogenic link between A? and Tau, a large knowledge gap exists in how A? pathogenically impinges on Tau. Our recently published and preliminary studies indicate that the Slingshot-1 homolog (SSH1)-Cofilin activation pathway and RanBP9 play critical roles in linking A? and Tau pathogenesis as well as their downstream neurotoxic signaling. Therefore, our central hypothesis is that RanBP9 and the Slingshot-Cofilin activation pathway not only mediate A?- induced neurotoxicity but also simultaneously promotes A? and Tau pathogenesis. By utilizing molecular, biochemical, cell biological, electrophysiological, viral, and histochemical tools, we propose to 1) test the effects of SSH1 inhibition as a potential therapeutic strategy to simultaneously reduce both A? and Tau pathogenesis; 2) validate the role of SSH1 and novel SSH1 inhibitors in A? secretion and Tau phosphorylation in primary neurons, and 3) determine the role of SSH1 and Cofilin activation status on Tau/MT dynamics and A? production in primary neurons.

Public Health Relevance

The defining pathological hallmark of Alzheimer?s disease (AD) is the accumulation of A? and Tau in brain associated with synapse loss, alterations in energy metabolism, inflammation of brain cells, and cognitive decline. This application utilizes integrated approaches in an effort to understand the molecular links between the A? and Tau pathologies as well as their neurotoxic actions. These studies are expected to shed novel insights to validating new therapeutic targets for AD by studying those that impinge on both A? and Tau simultaneously.