Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimers Disease

Abstract

Alzheimers disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (A{beta}) plaques and significant progressive memory loss. In AD, astrocytes are known to take up and clear A{beta} plaques. However, how A{beta} induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas A{beta}-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrate ammonia, end-product urea, and side-product putrescine. Gene-silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion, boosts urea cycle and eliminates aberrant putrescine and its toxic by-products ammonia, H2O2, and GABA to recover from reactive astrogliosis and memory impairment in AD model. Our findings implicate that astrocytic urea cycle exerts opposing roles of beneficial A{beta} detoxification and detrimental memory impairment in AD. We propose ODC1-inhibition as a promising therapeutic strategy for AD to facilitate removal of toxic molecules and prevent memory loss.