Ju YH, Bhalla M, Hyeon SJ, Oh JE, Yoo S, Chae U, Kwon J, Koh W, Lim J, Park YM, Lee J, Cho IJ, Lee H, Ryu H, Lee CJ. Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimer's disease. Cell Metab. 2022 Aug 2;34(8):1104-1120.e8. Epub 2022 Jun 22 PubMed.

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  1. In this important study, Ju et al. showed that under normal conditions, astrocytic urea metabolism is non-cyclic, and that it becomes cyclic in reactive astrocytes upon exposure to cellular stress, i.e., Aβ.

    It is well known that upon exposure to pathological stimuli, astrocytes become reactive and eliminate protein aggregates. However, the chronic cellular stress by Aβ and pathological Tau exposure leads to overactivation and the cells become neurotoxic reactive astrocytes. The current study is highly relevant because reactive astrocytes are widely found in many human neurodegenerative diseases, including AD (Liddelow et al., 2017). 

    In this context, we and others demonstrated that astrocyte senescence is linked to loss of beneficial function and gain of neurotoxic function that contributes to Alzheimer’s disease and frontotemporal dementia (Gaikwad et al., 2021; Cohen and Torres, 2019). It would be interesting to understand whether cyclic urea metabolism is linked to astrosenescence and AD brain pathology.

    Additionally, the authors demonstrated that astrocytic ornithine decarboxylase-1 (ODC1) is an important upstream enzyme for excessive production of GABA—the byproduct of urea cycle which causes neurotoxicity. Using DFMO (difluoromethylornithine) for inhibition of ODC1, they showed that ODC1 inhibition ameliorates behavioral impairments in an AD mouse model.

    It would have been better if the authors had also investigated whether other cellular stressors—such as exposure to pathological tau, oxidative stress, and aging—would also influence the astrocytes in the same fashion.

    The study also has many limitations, like use of DFMO as an ODC1 inhibitor (DFMO has been shown to have non-specific activities, side effects of DFMO, challenges in long-term inhibition of ODC1). Future studies are warranted to develop specific ODC1 inhibitors.

    In conclusion, the study by Ju et al. provides a better understanding of the involvement of astrocyte-urea metabolism in AD pathophysiology. A deeper understanding of urea metabolism in reactive astrocytes may prove to be critical in understanding mechanisms of neurodegeneration.

    References:

    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017 Jan 26;541(7638):481-487. Epub 2017 Jan 18 PubMed.

    Gaikwad S, Puangmalai N, Bittar A, Montalbano M, Garcia S, McAllen S, Bhatt N, Sonawane M, Sengupta U, Kayed R. Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia. Cell Rep. 2021 Jul 20;36(3):109419. PubMed.

    Cohen J, Torres C. Astrocyte senescence: Evidence and significance. Aging Cell. 2019 Jun;18(3):e12937. Epub 2019 Feb 27 PubMed.

    View all comments by Sagar Gaikwad

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