Isoform-specific roles of AMPK catalytic α subunits in Alzheimer’s disease

Zhao, Fanpeng; Wang, Qianqian; Zhu, Xiongwei

doi:10.1172/jci137908

Cited by 12 publications

(9 citation statements)

References 23 publications

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“…Increased AMPK phosphorylation has been observed in the brains of patients with AD and mice models. [ 41 , 42 ] Neurofibrillary tangles, aggregates of hyperphosphorylated tau protein, are the main pathological markers of AD and are regulated at numerous sites by AMPK. [ 43 , 44 ] In contrast, activation of AMPK decreases the accumulation of Aβ both in vitro and in vivo .…”

Section: Energy Balance Of Nerve Cell Microenvironment In Admentioning

confidence: 99%

Aberrant energy metabolism in Alzheimer’s disease

Jin

et al. 2022

Journal of Translational Internal Medicine

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To maintain energy supply to the brain, a direct energy source called adenosine triphosphate (ATP) is produced by oxidative phosphorylation and aerobic glycolysis of glucose in the mitochondria and cytoplasm. Brain glucose metabolism is reduced in many neurodegenerative diseases, including Alzheimer’s disease (AD), where it appears presymptomatically in a progressive and region-specific manner. Following dysregulation of energy metabolism in AD, many cellular repair/regenerative processes are activated to conserve the energy required for cell viability. Glucose metabolism plays an important role in the pathology of AD and is closely associated with the tricarboxylic acid cycle, type 2 diabetes mellitus, and insulin resistance. The glucose intake in neurons is from endothelial cells, astrocytes, and microglia. Damage to neurocentric glucose also damages the energy transport systems in AD. Gut microbiota is necessary to modulate bidirectional communication between the gastrointestinal tract and brain. Gut microbiota may influence the process of AD by regulating the immune system and maintaining the integrity of the intestinal barrier. Furthermore, some therapeutic strategies have shown promising therapeutic effects in the treatment of AD at different stages, including the use of antidiabetic drugs, rescuing mitochondrial dysfunction, and epigenetic and dietary intervention. This review discusses the underlying mechanisms of alterations in energy metabolism in AD and provides potential therapeutic strategies in the treatment of AD.

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Section: Energy Balance Of Nerve Cell Microenvironment In Admentioning

confidence: 99%

Aberrant energy metabolism in Alzheimer’s disease

Jin

et al. 2022

Journal of Translational Internal Medicine

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“…In order to explore the underlying mechanism of the memory improvement effects of MOTS-c, a recent study indicates up-regulation of brain AMPK activity in AD-associated synaptic failure. − Western blot experiments showed that the phosphorylation of AMPK was slightly increased in the hippocampus of Aβ 1–42 -treated mice. However, MOTS-c treatment significantly up-regulated the phosphorylation of AMPK, which is in line with behavioral experiment results ( p < 0.01 for LPS group vs LPS + MOTS-c group, Figure K; p < 0.05 for Aβ 1–42 group vs Aβ 1–42 + MOTS-c group, Figure L).…”

Section: Results and Discussionmentioning

confidence: 99%

Peripheral Administration of a Cell-Penetrating MOTS-c Analogue Enhances Memory and Attenuates Aβ_1–42- or LPS-Induced Memory Impairment through Inhibiting Neuroinflammation

Jiang

Chang

Nie

et al. 2021

ACS Chem. Neurosci.

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Background: MOTS-c is a 16-amino acid mitochondrial derivative peptide reported to be involved in regulating insulin resistance and obesity, osteoporosis and inflammatory responses. Accumulating evidences suggest that inhibiting neuroinflammation is a potential target in therapeutic or preventive strategies for Alzheimer's disease (AD). Due to the widespread distribution of MOTS in the CNS and its role in metabolism and immune system, previous reports also pointed out that MOTS-c may be effective as a therapeutic option toward the prevention of the aging processes. Therefore, it is important to understand the roles of MOTS-c in neuroinflammation. Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, western blotting, ELISA and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution of intranasal or intravenous MOTSc or MP (MOTS-c conjugated with cell penetrating peptides). Peptides drugs were synthesized by a standard Fmoc-based solid-phase synthetic method. Results: Central MOTS-c enhances object and location recognition memory formation and consolidation, and ameliorates the memory deficit induced by Aβ1-42 or LPS in NOR and OLR tasks, whereas dorsomorphin (AMPK inhibitor, i.p.) significantly blocked the memory-ameliorating effects of MOTS-c. Western blotting experiments showed that MOTS-c provided neuroprotection against LPS or Aβ1-42-induced neuroinflammation, which was related with phosphorylation of AMPK, but not MAPK including ERK, JNK and p38. The underlying mechanism of MOTS-c neuroprotection may be involved of inhibiting the activation of astrocytes and microglia and production of proinflammatory cytokines including TNF-α, IL-6, IL-1β, COX-2 and iNOS. In order to improve the brain intake of MOTS-c, we screen out (PRR)5, a cell penetrating peptides, as a carrier for MOTS-c into the brain. Then in NOR task, intranasal or intravenous MP, but not MOTS-c, showed good memory performance on memory formation, memory consolidation and memory impairment. Finally, compared with control and Rho-MOTS-c groups, significant fluorescence signals of Rho-MP were detected in the brain by NIR fluorescence imaging.

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“…The AMPK α2 subunit is predominantly expressed in skeletal muscle and cardiac myocytes ( Sakamoto et al, 2005 , 2006 ; Thomson et al, 2007 ). Isoform-specific roles of AMPK α1/AMPK α2 contribute to the pathogenesis of different diseases (e.g., cardiovascular disease ( Ahmad et al, 2005 ; Sakamoto et al, 2006 ; Zarrinpashneh et al, 2006 ; Arad et al, 2007 ), osteoclastogenesis ( Wang et al, 2016 ), and Alzheimer’s disease ( Zhao et al, 2020 )).…”

Section: Ampk: Structure and Regulationmentioning

confidence: 99%

AMPK and Pulmonary Hypertension: Crossroads Between Vasoconstriction and Vascular Remodeling

Zhao

Song

2021

Front. Cell Dev. Biol.

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Pulmonary hypertension (PH) is a debilitating and life-threatening disease characterized by increased blood pressure within the pulmonary arteries. Adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric serine-threonine kinase that contributes to the regulation of metabolic and redox signaling pathways. It has key roles in the regulation of cell survival and proliferation. The role of AMPK in PH is controversial because both inhibition and activation of AMPK are preventive against PH development. Some clinical studies found that metformin, the first-line antidiabetic drug and the canonical AMPK activator, has therapeutic efficacy during treatment of early-stage PH. Other study findings suggest the use of metformin is preferentially beneficial for treatment of PH associated with heart failure with preserved ejection fraction (PH-HFpEF). In this review, we discuss the “AMPK paradox” and highlight the differential effects of AMPK on pulmonary vasoconstriction and pulmonary vascular remodeling. We also review the effects of AMPK activators and inhibitors on rescue of preexisting PH in animals and include a discussion of gender differences in the response to metformin in PH.

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Isoform-specific roles of AMPK catalytic α subunits in Alzheimer’s disease

Cited by 12 publications

References 23 publications

Aberrant energy metabolism in Alzheimer’s disease

Aberrant energy metabolism in Alzheimer’s disease

Peripheral Administration of a Cell-Penetrating MOTS-c Analogue Enhances Memory and Attenuates Aβ_1–42- or LPS-Induced Memory Impairment through Inhibiting Neuroinflammation

AMPK and Pulmonary Hypertension: Crossroads Between Vasoconstriction and Vascular Remodeling

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Isoform-specific roles of AMPK catalytic α subunits in Alzheimer’s disease

Cited by 12 publications

References 23 publications

Aberrant energy metabolism in Alzheimer’s disease

Aberrant energy metabolism in Alzheimer’s disease

Peripheral Administration of a Cell-Penetrating MOTS-c Analogue Enhances Memory and Attenuates Aβ1–42- or LPS-Induced Memory Impairment through Inhibiting Neuroinflammation

AMPK and Pulmonary Hypertension: Crossroads Between Vasoconstriction and Vascular Remodeling

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Peripheral Administration of a Cell-Penetrating MOTS-c Analogue Enhances Memory and Attenuates Aβ_1–42- or LPS-Induced Memory Impairment through Inhibiting Neuroinflammation