The parent active award for this application for NOT-AG-18-039 ?Alzheimer's-focused administrative supplements? is to define the novel role and mechanisms of wound SPM biodegradation in the impairment of diabetic wound healing of the aged. Impeded resolution of chronic inflammation contributes substantially to the impairment of healing by the combination of aging and diabetes. Resolving chronic inflammation is pivotal in overcoming this impairment, and is attributable to the action of specialized pro-resolving lipid mediators (SPMs). Our prior research, including the active parent award, has identified a unique dysregulation, common to both Alzheimer's disease (AD) brains and diabetic wounds of the elderly, in the metabolic pathway leading to SPM biodegradation. Our long-term goal is to unravel mechanisms underlying the pathogenesis of both AD and chronic wounds and to develop effective therapies for these devastating diseases. Endogenous SPMs are biosynthesized enzymatically from essential polyunsaturated fatty acids. Two specific SPMs were identified in skin and brains: SPM1 (i.e., 14S,21R-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid) and neuroprotectin D1 (NPD1). Both SPM1 and NPD1 were diminished in brains of humans with AD or mouse AD models. We also identified the 15-hydroxyprostaglandin dehydrogenase (PGDH) degradation products of SPM1 and NPD1. We hypothesize that the exacerbated biodegradation of SPMs in brains contributes to AD pathogenesis. We will test this using mouse AD model, human neural cell models, PGDH inhibition and knockout, and our unique aqueous chiral (ac) LC-MS/MS lipidomics platform. The objective of this supplemental project is to initiate an exploration of the novel role and mechanisms of SPM biodegradation in AD pathogenesis.
Aim 1. Test the prediction that the biodegradation deactivates the ability of endogenous SPM1 and NPD1 to protect against and ameliorate AD pathogenesis. 1A) Determine the kinetics of SPMs and their biodegradants in brains of mouse AD model and control using acLC-MS/MS. 1B) Assess the activities of biodegradants of SPM1 and NPD1 on specific AD pathogenesis using human neural cell models.
Aim 2. Identify the key enzymatic pathway for SPM biodegradation in brains of mouse AD model and its role in AD pathogenesis. 2A) We will use inhibitors to decipher the roles of the enzyme for both SPM biodegradation and AD pathogenesis in mouse AD models. 2B) We will use mice with knockout of the key SPM degradation enzyme to verify the SPM biodegradation mechanism revealed by the enzyme inhibitors. Overall impact: This project will delineate the innovative SPM-biodegradation mechanism for AD pathogenesis. This mechanism is highly translational for the development of new therapeutics to prevent and ameliorate AD. The work proposed is within the scope of the active parent award that also aims to investigate SPM biodegradation as a mechanism for impaired repair and regeneration (but in active parent award, we focus on diabetic wounds of the aged), which meets the 3 criteria in NOT-AG-18-039 for this supplemental grant.
Alzheimer?s disease (AD) and its related dementias (ADRD) disable over 5 million aged population in USA alone and is present in about two-thirds of patients with dementia. The goal of this supplemental project is to conduct an initial exploration of the novel role and mechanisms of the biodegradation of specialized pro- resolving lipid mediators (SPMs) in AD pathogenesis. The mechanisms identified in this project will be highly translational for the development of new therapeutics to prevent and ameliorate AD and ADRD.
