The Role of the Urea Cycle in the Alzheimer's Disease Brain

ABSTRACT Alzheimer's Disease (AD) is a neurodegenerative disorder classified as the leading form of dementia in the elderly. Classical hallmarks of AD pathology believed to cause AD include Amyloid‐beta (Aβ) plaques as well as neurofibrillary tau tangles (NTT). However, research into these classical hallmarks has failed to account for a causative link or therapeutic success. More recently, metabolic hallmarks of AD pathology have become a popular avenue of research. Elevated urea and ammonia detected in cases of AD point towards a dysfunctional urea cycle involved in AD. This review covers the expansive body of literature surrounding the work of researchers deciphering the role of the urea cycle in AD pathology through the study of urea cycle enzymes, metabolites, and transporters in the AD brain. Urea cycle enzymes of interest in AD pathology include OTC, NOS isoforms, ARG1, ARG2, MAOB, and ODC, which all present as promising therapeutic targets. Urea metabolites indicated in AD pathology have varying concentrations across the regions of the brain and the different cell types (neurons, microglia, astrocytes). Finally, the role of UT‐B as a clearance modulator presents this protein as a key target for research in the role of the urea cycle in the AD brain. In the future, these key enzymes, pathways, and proteins relating to the urea cycle in AD should be further investigated to better understand the cell‐specific urea cycle profiles in the AD brain and uncover their therapeutic potential. image