Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer's disease mouse model

Lv, Junniao; Ma, Shuaipeng; Zhang, Xuefei; Zheng, Liangjun; Ma, Yuanhui; Zhao, Xuyang; Lai, Wenjia; Shen, Haoming; Wang, Qingsong; Ji, Jianguo

doi:10.1016/j.jprot.2014.07.028

Cited by 33 publications

(28 citation statements)

References 83 publications

(126 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies comparing differentially expressed proteins in the hippocampus of FAD mouse models to their corresponding Ntg controls have identified changes in the expression of proteins involved in processes such as autophagy, inflammation, and lipid metabolism, including APOE, PEA14, GFAP, and C1QB, among others 53–55 . In order to compare and contrast the results of our work with previous studies, we analyzed the hippocampal membrane proteome of AD and Ntg mice regardless of CFM status (n = 8/grp).…”

Section: Resultsmentioning

confidence: 99%

Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer’s disease mouse models

Neuner

Wilmott

Hoffmann

et al. 2017

Behavioural Brain Research

View full text Add to dashboard Cite

Alzheimer’s disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of ‘normal’ aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., GRIA1, GRM3, and SYN1), were altered in both ‘normal’ aging and AD. Pathway analysis highlighted HDAC4 as a regulator of observed protein changes in both genotypes and identified the REST epigenetic regulatory pathway and Gi intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins APOE and CLU. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD.

show abstract

Section: Resultsmentioning

confidence: 99%

Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer’s disease mouse models

Neuner

Wilmott

Hoffmann

et al. 2017

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…Luciferase reporter assays further confirmed Pea15a as a direct target of miR-155. Although Pea15 has previously been shown to be involved in various biological processes including cell proliferation, migration, differentiation, and apoptosis, and participates to regulate neurodegenerative diseases and cancers, 51,52,53,54,55,56,57 little is known about its role in cardiovascular diseases. Here we identify Pea15a as a novel target gene of miR-155 potentially contributing to sepsis-induced cardiac dysfunction by targeting apoptosis, thus suggesting that the miR-155/Pea15a pathway might serve as a potential therapeutic target for septic myocardial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miR-155 Protects Against LPS-induced Cardiac Dysfunction and Apoptosis in Mice

Wang

Bei

Huang

et al. 2016

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

Sepsis-induced myocardial dysfunction represents a major cause of death in intensive care units. Dysregulated microRNAs (miR)-155 has been implicated in multiple cardiovascular diseases and miR-155 can be induced by lipopolysaccharide (LPS). However, the role of miR-155 in LPS-induced cardiac dysfunction is unclear. Septic cardiac dysfunction in mice was induced by intraperitoneal injection of LPS (5 mg/kg) and miR-155 was found to be significantly increased in heart challenged with LPS. Pharmacological inhibition of miR-155 using antagomiR improved cardiac function and suppressed cardiac apoptosis induced by LPS in mice as determined by echocardiography, terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay, and Western blot for Bax and Bcl-2, while overexpression of miR-155 using agomiR had inverse effects. Pea15a was identified as a target gene of miR-155, mediating its effects in controlling apoptosis of cardiomyocytes as evidenced by luciferase reporter assays, quantitative real time-polymerase chain reaction, Western blot, and TUNEL staining. Noteworthy, miR-155 was also found to be upregulated in the plasma of patients with septic cardiac dysfunction compared to sepsis patients without cardiac dysfunction, indicating a potential clinical relevance of miR-155. The receiver-operator characteristic curve indicated that plasma miR-155 might be a biomarker for sepsis patients developing cardiac dysfunction. Therefore, inhibition of miR-155 represents a novel therapy for septic myocardial dysfunction.

show abstract

“…Second, apolipoprotein E (ApoE) is necessary to achieve phagocytosis of Aβ by astrocytes, it is then possible that bryostatin-1 acts through a reduction of ApoE expression. Third, leucine-rich glioma inactivated 3 and phosphoprotein enriched in astrocytes-15 were shown to participate in Aβ uptake by astrocytes (Lv et al, 2014;Okabayashi & Kimura, 2008) and could be involved in the observed reduction. In contrast with bryostatin-1, JQ1 had no impact in Aβ endocytosis, but induced a drastic reduction in zymosan phagocytosis, with an additive effect when bryostatin-1 and JQ1 were used together suggesting a different mechanism of action for the two studied LRA.…”

Section: Discussionmentioning

confidence: 91%

HIV‐1 infection and latency‐reversing agents bryostatin‐1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes

Proust

Barat

Lebœuf

et al. 2020

Glia

View full text Add to dashboard Cite

Since the introduction of the combined antiretroviral therapy, HIV‐1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general population. Nevertheless, various age‐related pathologies such as neurocognitive disorders have emerged as serious complications. A “shock and kill” strategy using latency‐reversing agents (LRA) to reactivate HIV‐1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aβ) deposition is a feature of HIV‐1‐infected brains, we investigated the consequences of HIV‐1 infection and treatment with two LRA (bryostatin‐1 and JQ1) on the capacity of human astrocytes to engulf and clear Aβ. We show here that HIV‐1‐infected astrocytes accumulate a very high amount of Aβ compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin‐1 induces a reduction in Aβ endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aβ‐loaded microvesicles. Thus, both HIV‐1 infection and treatment with some LRA could contribute to the reported Aβ accumulation in the brain of HIV‐1‐infected persons.

show abstract

Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer's disease mouse model

Cited by 33 publications

References 83 publications

Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer’s disease mouse models

Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer’s disease mouse models

Inhibition of miR-155 Protects Against LPS-induced Cardiac Dysfunction and Apoptosis in Mice

HIV‐1 infection and latency‐reversing agents bryostatin‐1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes

Contact Info

Product

Resources

About