Chronic hypoxia of endothelial cells boosts HIF-1α-NLRP1 circuit in Alzheimer’s disease

Jung, Eunyoung; Kim, Ye Eun; Jeon, Hui Su; Yoo, Myeongjong; Kim, Minsu; Kim, Young‐Myeong; Koh, Seong‐Ho; Choi, Yoon Kyung

doi:10.1016/j.freeradbiomed.2023.05.011

Cited by 9 publications

(10 citation statements)

References 33 publications

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“…In 3×Tg mice without cerebral microinfarcts, capillary loss was related to aging or hypoxia that increased HIF-1α stability. This result is supported by previous studies showing that HIF-1α is increased in microvessels from AD mice, including 3×Tg (Grammas et al, 2011;Jung et al, 2023). The increase in HIF-1α reduced PGC-1α and c-Myc activities and subsequently reduced TFAM.…”

Section: Discussionsupporting

confidence: 86%

PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts

Wang,

Zhang,

Hongpaisan

2023

Front. Aging Neurosci.

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BackgroundCurrent evidence suggests that microvessel disease is involved in Alzheimer’s disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevents degradation and promotes the translation of mitochondrial Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF) mRNAs.MethodsTo induce brain microinfarcts, we injected triple transgenic (3×Tg) and wild-type (WT) control mice with microbeads (20 μm caliber) into common carotid arteries, with or without the DCPLA-ME (methyl-ester) for 2 weeks. After water maze training, mice at 16 months old were examined for confocal immunohistochemistry at a single cell or microvessel level in the hippocampal CA1 area, important for spatial memory storage, and in the dorsal hippocampus by western blots.ResultsIn 3×Tg mice without cerebral microinfarcts, an accelerating age-related increase in (mild) oxidative stress and hypoxia inducible factor (HIF)-1α, but a reduction in VEGF, mitochondrial transcription factor A (TFAM), and MnSOD were associated with capillary loss. The change was less pronounced in arterioles. However, in 3×Tg mice with cerebral microinfarcts, increasing arteriolar diameter and their wall cells were related with the strong oxidative DNA damage 8-hydroxy-2′-deoxyguanosine (8-OHdG), apoptosis (cleaved caspase 3), and sustained hypoxia (increased HIF-1α and VEGF/PKCε/extracellular signal regulated kinase or ERK pathway). Microocclusion enhanced the loss of the synaptic marker spinophilin, astrocytic number, and astrocyte-vascular coupling areas and demyelination of axons. DCPLA-ME prevented spatial memory defect; strong oxidative stress-related apoptosis; sustained hypoxia (by reducing HIF-1α and VEGF); and exaggerated cell repair in arteriolar walls, pericapillary space dilation, neuro-glial-vascular disruption, and demyelination.ConclusionIn conclusion, in 3×Tg mice with cerebral microinfarcts, sustained hypoxia (increased HIF-1α and VEGF signals) is dominant with arteriolar wall thickening, and DCPLA has a protective effect on sustained hypoxia.

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Section: Discussionsupporting

confidence: 86%

PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts

Wang,

Zhang,

Hongpaisan

2023

Front. Aging Neurosci.

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“…Meanwhile, the level of hypoxia-inducible factor 1 alpha (HIF-1α) in tumors was also investigated after different treatments. HIF-1α is a specific marker of tumor hypoxia status, which is proportional to the hypoxia degree in tumor tissues. ,− The immunofluorescence results of HIF-1α showed that the level of HIF-1α was significantly higher in Lip SOR - and Lip TPZ/SOR -treated tumors than that in saline-treated tumors (Figure e). The statistical analysis of the HIF-1α-positive area was also performed, and the results are shown in Figure f.…”

Section: Resultsmentioning

confidence: 99%

Sorafenib-Encapsulated Liposomes to Activate Hypoxia-Sensitive Tirapazamine for Synergistic Chemotherapy of Hepatocellular Carcinoma

Zhao,

Dai,

Zhan

et al. 2024

ACS Appl. Mater. Interfaces

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Combination therapy with the synergistic effect is an effective way in cancer chemotherapy. Herein, an antiangiogenic sorafenib (SOR) and hypoxia-activated prodrug tirapazamine (TPZ)-coencapsulated liposome (Lip TPZ/SOR ) is prepared for chemotherapy of hepatocellular carcinoma (HCC). SOR is a multi-target tyrosine kinase inhibitor that can inhibit tumor cell proliferation and angiogenesis. The antiangiogenesis effect of SOR can reduce oxygen supply and aggravate tumor hypoxia, which is able to activate hypoxia-sensitive prodrug TPZ, exhibiting the synergistic antitumor effect. Lip TPZ/SOR at different molar ratios of TPZ and SOR can significantly inhibit the proliferation of hepatocellular carcinoma cells. The mole ratio of TPZ and SOR was optimized to 2:1, which exhibited the best synergetic antitumor effect. The synergistic antitumor mechanism of SOR and TPZ was also investigated in vivo. After treated with SOR, the number of vessels was decreased, and the degree of hypoxia was aggravated in tumor tissues. What is more, in the presence of SOR, TPZ could be activated to inhibit tumor growth. The combination of TPZ and SOR exhibited an excellent synergistic antitumor effect. This research not only provides an innovative strategy to aggravate tumor hypoxia to promote TPZ activation but also paints a blueprint about a new nanochemotherapy regimen for the synergistic chemotherapy of HCC, which has excellent biosafety and bright clinical application prospects.

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“…The risk of experiencing both acute and chronic intermittent hypoxia increases with age. Accumulating evidence of recent years supports the notion that a hypoxic or ischemic episode in the brain can serve as a crucial trigger for the onset and progression of dementia and/or Alzheimer's disease [45][46][47]. Consequently, it is of utmost importance to study the age-related characteristics of neuronal responses to the detrimental effects of hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Unravelling the Collective Calcium Dynamics of Physiologically Aged Astrocytes under a Hypoxic State In Vitro

Mitroshina,

Krivonosov,

Pakhomov

et al. 2023

IJMS

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Astrocytes serve many functions in the brain related to maintaining nerve tissue homeostasis and regulating neuronal function, including synaptic transmission. It is assumed that astrocytes are crucial players in determining the physiological or pathological outcome of the brain aging process and the development of neurodegenerative diseases. Therefore, studies on the peculiarities of astrocyte physiology and interastrocytic signaling during aging are of utmost importance. Calcium waves are one of the main mechanisms of signal transmission between astrocytes, and in the present study we investigated the features of calcium dynamics in primary cultures of murine cortical astrocytes in physiological aging and hypoxia modeling in vitro. Specifically, we focused on the assessment of calcium network dynamics and the restructuring of the functional network architecture in primary astrocytic cultures. Calcium imaging was performed on days 21 (“young” astrocyte group) and 150 (“old” astrocyte group) of cultures’ development in vitro. While the number of active cells and frequency of calcium events were decreased, we observed a reduced degree of correlation in calcium dynamics between neighboring cells, which was accompanied by a reduced number of functionally connected cells with fewer and slower signaling events. At the same time, an increase in the mRNA expression of anti-apoptotic factor Bcl-2 and connexin 43 was observed in “old” astrocytic cultures, which can be considered as a compensatory response of cells with a decreased level of intercellular communication. A hypoxic episode aggravates the depression of the connectivity of calcium dynamics of “young” astrocytes rather than that of “old” ones.

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Chronic hypoxia of endothelial cells boosts HIF-1α-NLRP1 circuit in Alzheimer’s disease

Cited by 9 publications

References 33 publications

PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts

PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts

Sorafenib-Encapsulated Liposomes to Activate Hypoxia-Sensitive Tirapazamine for Synergistic Chemotherapy of Hepatocellular Carcinoma

Unravelling the Collective Calcium Dynamics of Physiologically Aged Astrocytes under a Hypoxic State In Vitro

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