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

Ju, Yeon Ha; Bhalla, Mridula; Hyeon, Seung Jae; Oh, Ju Eun; Yoo, Seonguk; Chae, Uikyu; Kwon, Jea; Koh, Wuhyun; Lim, Jiwoon; Park, Yongmin Mason; Lee, Jung‐Hee; Cho, Il‐Joo; Lee, Hyunbeom; Ryu, Hoon; Lee, C Justin

doi:10.1016/j.cmet.2022.05.011

Cited by 63 publications

(44 citation statements)

References 43 publications

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“…The alpha glycerophosphate ester, an esterified form of glycerol, increased by ~60 fold. Urea level, known to increase risk of Alzheimer’s and other forms of dementia (34, 58, 59), increased drastically by 2,183-fold in the fetal brain of Cav1 -null compared to WT mice suggested that Cav1 had a role in regulating brain urea which is independent of circulating urea (60).…”

Section: Resultsmentioning

confidence: 99%

“…Metabolic and epigenetic changes in the brain are associated with the risk of AD (25,(29)(30)(31)(32)(33). Abnormal level of urea, cholesterol, serine and other metabolites in the brain cholesterol increases risk of AD (34)(35)(36)(37). Besides roles in the regulating urea (38) and serine (39), Cav1 plays a role to regulate cellular homeostasis of cholesterol (7,(40)(41)(42).…”

Section: Introductionmentioning

confidence: 99%

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Role of Caveolin 1 in metabolic programming of fetal brain

Islam

Behura

2022

Preprint

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Caveolin-1 (Cav1) encodes a major protein of the lipid rafts, called caveolae, which are plasma membrane invaginations found in most cells of mammals. Cav1-null mice, at an early adult age, exhibit symptoms that are hallmarks of Alzheimers disease, and show brain aging similar to that of one and half year old wildtype mice. In the present study, integrative analysis of metabolomics, transcriptomics, epigenetics and single cell data was performed to test the hypothesis that metabolic deregulation of fetal brain due to lack of Cav1 influenced brain aging in these mice. The results of this study show that lack of Cav1 deregulated lipid and amino acid metabolism in the fetal brain. Genes associated with the deregulated metabolites were significantly altered in specific glial cells of the fetal brain, and epigenetically altered in a coordinated manner with specific genes of mouse epigenetic clock. The interaction between metabolic and epigenetic changes in the fetal brain altered gene expression of the brain at old age. Together, these results suggested that metabolic deregulation in the fetal life elicited an epigenetic memory that altered brain programming for aging in Cav1-null mice.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Caveolin 1 in metabolic programming of fetal brain

Islam

Behura

2022

Preprint

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“…Astrocytes are a nonneuronal cell type in the central nervous system (CNS) that control CNS homeostasis, synapse formation, and synaptic function. Under pathological conditions, astrocytes adopt either neuroprotective (14) or neurotoxic phenotypes (15)(16)(17). Dysregulated neurotoxic astrocytes may participate in the pathogenesis of various neurodegenerative diseases (18).…”

Section: Introductionmentioning

confidence: 99%

Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy

et al. 2022

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Astrocyte abnormalities have received great attention for their association with various diseases in the brain but not so much in the eye. Recent independent genome-wide association studies of glaucoma, optic neuropathy characterized by retinal ganglion cell (RGC) degeneration, and vision loss found that single-nucleotide polymorphisms near the ABCA1 locus were common risk factors. Here, we show that Abca1 loss in retinal astrocytes causes glaucoma-like optic neuropathy in aged mice. ABCA1 was highly expressed in retinal astrocytes in mice. Thus, we generated macroglia-specific Abca1 -deficient mice (Glia-KO) and found that aged Glia-KO mice had RGC degeneration and ocular dysfunction without affected intraocular pressure, a conventional risk factor for glaucoma. Single-cell RNA sequencing revealed that Abca1 deficiency in aged Glia-KO mice caused astrocyte-triggered inflammation and increased the susceptibility of certain RGC clusters to excitotoxicity. Together, astrocytes play a pivotal role in eye diseases, and loss of ABCA1 in astrocytes causes glaucoma-like neuropathy.

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“…Astrocytes are the most abundant cell types in the brain and play a vital role in both physiological [6,7,8] and pathological [9,10,11,12,13] conditions. The astrocytic Ca 2+ signaling is critically involved in various gliotransmitter releases such as glutamate [14], GABA [15], ATP [16], and D-serine [17], which are critical for glia-neuron communication.…”

Section: Introductionmentioning

confidence: 99%

Dopamine-induced astrocytic Ca2+ signaling in mPFC is mediated by MAO-B in young mice, but by dopamine receptors in adult mice

Kim¹,

Kwon

Park³

et al. 2022

Preprint

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Dopamine (DA) plays a vital role in brain physiology and pathology such as learning and memory, motor control, neurological diseases, and psychiatric diseases. In neurons, it has been well established that DA increases or decreases intracellular cyclic AMP (cAMP) through D1-like or D2-like dopamine receptors, respectively. In contrast, astrocytes respond to DA via Ca2+ signaling and regulate synaptic transmission and reward systems. Previous studies suggest various molecular targets such as MAO-B, D1R, or D1R-D2R heteromer to modulate astrocytic Ca2+ signaling. However, which molecular target is utilized under what physiological condition remains unclear. Here, we show that DA-induced astrocytic Ca2+ signaling pathway switches during development: MAO-B is the major player at a young age (5 - 6 weeks), whereas DA receptors (DARs) are responsible for the adult period (8 - 12 weeks). DA-mediated Ca2+ response in the adult period was decreased by either D1R or D2R blockers, which are primarily known for cyclic AMP signaling (Gs and Gi pathway, respectively), suggesting that this Ca2+ response might be mediated through Gq pathway by D1R-D2R heterodimer. Moreover, DAR-mediated Ca2+ response was not blocked by TTX, implying that this response is not a secondary response caused by neuronal activation. Our study proposes an age-specific molecular target of DA-induced astrocytic Ca2+ signaling: MAO-B in young mice and DAR in adult mice.

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

Cited by 63 publications

References 43 publications

Role of Caveolin 1 in metabolic programming of fetal brain

Role of Caveolin 1 in metabolic programming of fetal brain

Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy

Dopamine-induced astrocytic Ca2+ signaling in mPFC is mediated by MAO-B in young mice, but by dopamine receptors in adult mice

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