Approximately 4.5 million Americans are affected by Alzheimer's disease (AD) today and up to 13 million will be affected by 2050. At present, there is no preventive or therapeutic treatment for AD, and disease-modifying compounds tested in clinical trials have been unsuccessful. These setbacks underscore the urgency of identifying novel pathological mechanisms that can be targeted to prevent or treat AD. Two pathologic processes are intimately associated with the development and progression of AD: inflammation and oxidative stress. Although these phenomena are complex, they generate a common molecular species of reactive keto-aldehydes. These reactive aldehydes are produced as a result of either lipid peroxidation associated with oxidative stress or through increased enzymatic activity of the cyclooxygenases (COX-1 and COX-2), both of which are induced in inflammatory states. Importantly, these reactive aldehydes form stable covalent adducts that disrupt or modify protein function, localization, and aggregation. We have previously demonstrated that levels of these adducts, or levuglandins (LGs), in hippocampus of AD patients correlate with the Braak scale of AD severity. Importantly, formation of LG adducts on amyloid b (Ab) peptide increases its rate of oligomerization and neurotoxicity. Recently, we have identified a class of small molecules that can bind to LGs with very high affinity, without inhibiting either COX-1 or COX-2 activity, and block LG-adduction to proteins in brain.
In AIM 1, we will test whether administration of LG scavenger will act in a preventive manner to delay the onset of memory deficits that begin in pre-plaque AD mice. Separate cohorts will be analyzed for levels of LGs by liquid chromatography tandem mass spectrometry, oxidative damage, Ab peptide levels, and inflammatory markers.
In AIM 2, we will investigate whether administration of LG scavenger will have a beneficial therapeutic effect in aging APPS mice that already have cognitive deficits, an established plaque load, tau phosphorylation, and synaptic deficits, a situation similar to that of the MCI or AD patient. Data generated from these studies will provide a critical proof of concept validating a preventive as well as therapeutic approach for this small molecule scavenger in a well-established and well-characterized pre-clinical AD model. It will also provide evidence for a new pharmacological target for development of drugs aimed at reducing levels of reactive aldehydes in AD.
In this proposal, we will determine whether treating AD mice with a scavenger of reactive gamma ketoaldehydes can inhibit formation of LG adducts in brain, reduce levels of Ab oligomers, and prevent onset of behavioral and synaptic deficits in young preplaque AD mice and attenuate disease severity in aging AD mice. Successful completion of these pre-clinical studies will validate a novel drug target for AD and demonstrate that scavenging reactive aldehydes in brain prevents development of behavioral deficits in a well established animal model of AD.
|Woodling, Nathaniel S; Wang, Qian; Priyam, Prachi G et al. (2014) Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling. J Neurosci 34:5882-94|