M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer’s disease genes and improving memory

Volmar, Claude‐Henry; Salah-Uddin, Hasib; Janczura, Karolina J.; Halley, Paul; Lambert, Guerline; Wodrich, Andrew P.K.; Manoah, Sivan; Patel, Nidhi; Sartor, Gregory C.; Mehta, Neil; Miles, Nancy T.H.; Desse, Sachi; Dorcius, David; Cameron, Michael D.; Wahlestedt, Claes

doi:10.1073/pnas.1707544114

Cited by 57 publications

(48 citation statements)

References 87 publications

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“…This information showed that anti-neuroinflammation was an important mechanism underlying the prevention of BHB to postsepsis cognitive impairment. Previous studies showed that BHB was an endogenous histone deacetylase inhibitor [18], and sepsis induced obvious changes of histone deacetylases [25][26][27]. Thus, histone deacetylases were the possible downstream molecules of HCA2 and MCT2.…”

Section: Discussionmentioning

confidence: 97%

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Subcutaneous administration of β-hydroxybutyrate improves learning and memory of sepsis surviving mice

et al. 2020

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Post-sepsis cognitive impairment is one of the major sequelae in sepsis survivors. Its prevention remains clinically challenging. Here we tested the effects and underlying mechanisms of exogenous β-hydroxybutyrate (BHB) on post-sepsis cognitive impairment. We found that subcutaneous administration of BHB increased survival and body weight recovery of sepsis mice and improved learning and memory of sepsis surviving mice in a cecal ligation and perforation-induced sepsis model. Additionally, the improvement of learning and memory of sepsis surviving mice was still detected even if BHB was administrated at the late stage of sepsis. In contrast, glucose solution did not show similar effects. Mechanistically, subcutaneous administration of BHB increased the BHB level of hippocampus, and limited neuroinflammation and neuroplasticity damage in sepsis mice. Intracerebroventricular administration of BHB also alleviated neuroinflammation and cognitive impairment of sepsis surviving mice. In the coculture of neurons, astrocytes, and BV2 cells (a microglial cell line), knocking down the expression of microglial HCA2 (BHB receptor) via a specific shRNA reduced the protection of BHB to lipopolysaccharide-induced inflammatory response and neuron damage more significantly than knocking down neuronal MCT2 (BHB transporter). These data showed that (1) BHB was a potential pharmacological adjunct treatment for prevention of post-sepsis cognitive impairment and (2) inhibiting neuroinflammation via HCA2 was an important mechanism.

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Section: Discussionmentioning

confidence: 97%

“…A novel object recognition test (NOR) was conducted during the 14 th and 15 th days after CLP in a 30×30×20-cm field following the reported protocol [17,18]. The test consisted of two phases: a familiarization and a test phase.…”

Section: Novel Object Recognitionmentioning

confidence: 99%

Subcutaneous administration of β-hydroxybutyrate improves learning and memory of sepsis surviving mice

et al. 2020

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“…In our experiments, we have detected the expression of tagged vsps in cell lines treated with splitomicin more often than treated with TSA, Apicidin, M344, and NaPB, when compared to untreated controls. Apicidin [10], TSA [11], NaPB [12], and M344 [13] are known to inhibit NAD + independent histone deacetylases that belong to class I HDACs. A homologue of class I HDAC has been identified in the Giardia genome database and previous reports have indicated that this enzyme can be inhibited by TSA, Apicidin, and NaPB [6,8].…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors induce expression of chromosomally tagged variant-specific surface protein genes in Giardia lamblia

Orozco

Garlapati

2020

BMC Res Notes

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Objective: RNA interference and miRNA mediated mechanisms have been proposed to explain the expression of a specific variant of VSP at a time on the surface of Giardia lamblia. Recently, epigenetic mechanisms involving histone acetylations have been proposed to explain the process of vsp gene switching in Giardia lamblia. However, due to the limited availability of specific antibodies for all the vsp variants present in the genome, it was difficult to monitor vsp gene switching. In this study, we have used an endogenous tagging method to tag specific vsp genes vsp1267 and vsp9B10A with a sequence encoding hemagglutinin (HA) epitope at the 3′end of the coding sequences without altering the 5′ upstream elements. With this method, we have monitored the expression of the tagged vsp genes in cells treated with histone deacetylase inhibitors using RT-PCR. Results:Our results show that vsp1267-3XHA can be induced by treatment with sodium 4-phenylbutyrate, M344 and splitomicin but not by apicidin and Trichostatin A, while vsp9B10A-3XHA expression can be induced by Trichostatin A and splitomicin but not by sodium 4-phenylbutyrate, M344 and apicidin. The induced expression of these variants was not due to growth inhibition. These results support the role of histone acetylations in vsp expression.

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“…Another important and unique feature of the presented protocol is its full compatibility with downstream western blot analysis tools and others if so desired. Histone proteins are detected at ~15 kDa 13,22,23 and, similarly to other small molecular weight proteins, have been proven challenging to detect by standard immunoblotting techniques. The use of a high-performance and high-throughput transfer system in combination with optimal resolution protein gels allows for the maintenance of protein native confirmation (in the absence of SDS) and activity in the absence of SDS and high transfer efficiency of the low molecular weight histone proteins, thus assuring a reliable histone PTM quantification.…”

Section: Discussionmentioning

confidence: 99%

Purification of H3 and H4 Histone Proteins and the Quantification of Acetylated Histone Marks in Cells and Brain Tissue

Janczura

Volmar

Wahlestedt

2018

JoVE

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In all eukaryotic organisms, chromatin, the physiological template of all genetic information, is essential for heredity. Chromatin is subject to an array of diverse posttranslational modifications (PTMs) that mostly occur in the amino termini of histone proteins (i.e., histone tail) and regulate the accessibility and functional state of the underlying DNA. Histone tails extend from the core of the nucleosome and are subject to the addition of acetyl groups by histone acetyltransferases (HATs) and the removal of acetyl groups by histone deacetylases (HDACs) during cellular growth and differentiation. Specific acetylation patterns on lysine (K) residues on histone tails determine a dynamic homeostasis between transcriptionally active or transcriptionally repressed chromatin by (1) influencing the core histone assembly and (2) recruiting synergistic or antagonistic chromatin-associated proteins to the transcription site. The fundamental regulatory mechanism of the complex nature of histone tail PTMs influences the majority of chromatin-templated processes and results in changes in cell maturation and differentiation in both normal and pathological development. The goal of the current report is to provide novices with an efficient method to purify core histone proteins from cells and brain tissue and to reliably quantify acetylation marks on histones H3 and H4.

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M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer’s disease genes and improving memory

Cited by 57 publications

References 87 publications

Subcutaneous administration of β-hydroxybutyrate improves learning and memory of sepsis surviving mice

Subcutaneous administration of β-hydroxybutyrate improves learning and memory of sepsis surviving mice

Histone deacetylase inhibitors induce expression of chromosomally tagged variant-specific surface protein genes in Giardia lamblia

Purification of H3 and H4 Histone Proteins and the Quantification of Acetylated Histone Marks in Cells and Brain Tissue

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