Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer’s disease

Abstract

Alzheimers disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (Aβ) plaques and significant progressive memory loss. In AD, astrocytes are known to take up and clear Aβ plaques. However, how Aβ induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas Aβ-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 Aβ 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.

Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

“…In our previous studies, we have demonstrated how common molecular pathways such as MAOB-dependent putrescine degradation and GABA production are shared, even though the triggering factors are different ( Chun and Lee, 2018 ; Chun et al, 2020 ; Heo et al, 2020 ; Jo et al, 2014 ; Nam et al, 2020 ; Pandit et al, 2020 ; Shim et al, 2019 ). We have reported that autophagic degradation pathway is commonly triggered by pathogenic molecules such as diphtheria toxin, Aβ, cytokines, damaged tissue debris, and viral infections, which usually accompany neuroinflammation ( Chun et al, 2020 ; Ju et al, 2021 ). Under pathological conditions, astrocytes take up or internalize these toxic molecules to degrade them and subsequently turn on the urea cycle to convert the accumulating toxic ammonia to less toxic urea ( Cohen, 1981 ; Ju et al, 2021 ; Meijer et al, 1990 ; Morris, 2002 ).…”

“…We have reported that autophagic degradation pathway is commonly triggered by pathogenic molecules such as diphtheria toxin, Aβ, cytokines, damaged tissue debris, and viral infections, which usually accompany neuroinflammation ( Chun et al, 2020 ; Ju et al, 2021 ). Under pathological conditions, astrocytes take up or internalize these toxic molecules to degrade them and subsequently turn on the urea cycle to convert the accumulating toxic ammonia to less toxic urea ( Cohen, 1981 ; Ju et al, 2021 ; Meijer et al, 1990 ; Morris, 2002 ). The net consequence of this degradation and turning-on of the urea cycle is the production of putrescine, which further turns on MAOB-dependent production of GABA ( Ju et al, 2021 ).…”

“…Under pathological conditions, astrocytes take up or internalize these toxic molecules to degrade them and subsequently turn on the urea cycle to convert the accumulating toxic ammonia to less toxic urea ( Cohen, 1981 ; Ju et al, 2021 ; Meijer et al, 1990 ; Morris, 2002 ). The net consequence of this degradation and turning-on of the urea cycle is the production of putrescine, which further turns on MAOB-dependent production of GABA ( Ju et al, 2021 ). Of note, a recent study has reported that MAOB, which is mainly expressed in astrocytes, is elevated in transcriptionally profiled hypothalamic cells of DIO mice ( Rossi et al, 2019 ).…”

Visualizing cancer-originated acetate uptake through MCT1 in reactive astrocytes demarcates tumor border and extends survival in glioblastoma patients

“…We have recently demonstrated that putrescine, the source of astrocytic GABA, is increased via the urea cycle and polyamine metabolism in reactive astrocytes (Ju, 2021). To test whether acetate alone is associated with the urea cycle and polyamine metabolism, we measured the mRNA level of carbamoyl phosphate synthetase 1 (CPS1), the first enzyme of the urea cycle, and ornithine decarboxylase 1 (ODC1), the key enzyme behind polyamine biosynthesis converting ornithine into putrescine.…”

Caspase-dependent apoptosis induces reactivation and gliogenesis of astrocytes in adult mice

“…Recently, it has been shown that severely reactive astrocytes exhibit neurotoxicity by generating H 2 O 2 through the monoamine oxidase B (MAOB) is an enzyme involved in the production of GABA in astrocytes. GABA released from reactive astrocytes affects nearby neurons, and increased enzyme activity of MAOB has been reported in neurodegenerative disease models such as Parkinson's disease (Mallajosyula et al, 2008) and Alzheimer's disease (Chun et al, 2020;Ju et al, 2022). There may be steps in the process of astrocyte reactivation, and follow-up studies are needed to classify these steps (Escartin et al, 2021).…”