Signaling Pathways Regulating Amyloid Precursor Protein and Abeta Generation: Roles for Isoprostane-Induced Thromboxane Receptor Signaling and Chronic Akt Activation in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease pathologically marked by neurofibrillary tangles, senile plaques, inflammation, and oxidative stress ultimately culminating in neuronal cell loss. Senile plaques are composed of aggregated amyloid-beta (Abeta) peptides, which are cleaved from a larger protein known as the amyloid precursor protein (APP). The regulation of APP and Abeta generation is thought to be the central initiator of AD pathogenesis. Consequently, modulation of this pathway is of therapeutic importance for AD. Both cardiovascular disease and diabetes increase risk for AD and share many common risk factors with AD. These diseases also share common disease modifying pathways. In the work outlined here, two signaling pathways involved in cardiovascular disease and diabetes are linked to APP metabolism, Abeta generation and amyloid pathology. Isoprostanes, products of lipid peroxidation, are elevated in conditions of oxidative stress, such as heart disease and diabetes and are also elevated in human AD patients and mouse models of AD. The isoprostane isoform, iPF2alpha-III, can activate the thromboxane (TP) receptor and promote atherosclerotic plaque formation in cardiovascular disease. Our studies show that iPF2alpha-III-induced TP receptor activation can also promote AD amyloid pathology in mice by initiating downstream signaling events that post-transcriptionally stabilize APP mRNA, resulting in more substrate for the proteolytic cleavage reactions that generate Abeta. TP receptor antagonists have been developed for the treatment of cardiovascular disease. Here, we used both rational design and high throughput screening to develop brain penetrable TP receptor antagonists that may also be therapeutically beneficial for AD. Insulin signaling, which is impaired in insulin resistance and type 2 diabetes, can also regulate trafficking and secretion of APP. Our work demonstrates that chronic activation of Akt, a downstream mediator of the insulin signaling pathway, can cause feedback inhibition of this pathway and lead to defects in trafficking of APP and APP metabolites. Both TP receptor activation and insulin signaling, in addition to their known roles in cardiovascular disease and diabetes, can also regulate APP at many levels along its biogenesis and metabolism and ultimately influence AD pathology.