A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model

Campagna, Jesus; Spilman, Patricia; Jagodzinska, Barbara; Bai, Dongsheng; Hatami, Asa; Zhu, Chunni; Bilousova, Tina; Jun, Michael; Elias, Chris Jean; Pham, Johnny D.; Cole, Gregory M.; LaDu, Mary Jo; Jung, Michael E.; Bredesen, Dale E.; John, Varghese

doi:10.1038/s41598-018-35687-8

Cited by 26 publications

(15 citation statements)

References 71 publications

(80 reference statements)

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“…Finally, a first-in-class small molecule, apolipoprotein E4 (ApoE4)-targeted SIRT1 A03, showed SIRT1-enhancing effects in the hippocampus of 5XFAD-ApoE4 AD model mice improving their performance in cognitive tasks. The neurotoxic SIRT2 levels were not significantly affected ( Campagna et al, 2018 ).…”

Section: Sirt1 and Sirt2 In Alzheimer’s Diseasementioning

confidence: 99%

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021

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Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.

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Section: Sirt1 and Sirt2 In Alzheimer’s Diseasementioning

confidence: 99%

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

2021

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“…It has been reported that Human APOE4 could modulate the expression of Sirtuin 1 in brain regions of targeted replacement apoE mice 53 . In addition, a small molecule APOE4 − targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model 54 , suggesting the potential APOE4 and Sirt1 pathways. It is worth nothing that Sirt1 was recently reported that playing critical role to preventing autoimmunity and participate in sepsis progress 55 , 56 .…”

Section: Discussionmentioning

confidence: 99%

Presence of the apolipoprotein E-ε4 allele is associated with an increased risk of sepsis progression

Shao

Zhao

Zhang

et al. 2020

Sci Rep

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Growing evidence indicated that single nucleotide polymorphisms (SNPs) in the apolipoprotein E (APOE) gene are related to increase the risk of many inflammatory-related diseases. However, few genetic studies have associated the APOE gene polymorphism with sepsis. This study was to investigate the clinical relevance of the APOE gene polymorphism in the onset and progression of sepsis. A multicenter case–control association study with a large sample size (601 septic patients and 699 healthy individuals) was conducted. Clinical data showed that the APOEε4 allele was overrepresented among all patients with septic shock (p = 0.031) compared with sepsis subtype, suggesting that APOEε4 allele may associated with increased susceptibility to the progression of sepsis. Moreover, the APOE mRNA levels decreased after lipopolysaccharide (LPS) stimulation in cells in culture. Then 21 healthy individuals to extract PBMC for genotype grouping (APOE4+ group 8; APOE4− group 13) was selected to evaluate the effect on APOE level, and results showed that the expression level of APOE in APOE4+ group and APOE4− group did not differ in mRNA levels after an LPS challenge, but the protein levels in APOE4+ group decreased slower than that in APOE4− group, and this process was accompanied by the upregulation of proinflammatory cytokines. These results provide evidence that the APOEε4 allele might be associated with the development of sepsis and a potential risk factor that can be used in the prognosis of sepsis.

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“…The major genetic risk factor in AD is apolipoprotein-E4 (ApoE4), which has a significant potential to reduce Sirtuin 1 ( Sirt1 ) expression. This sirt1 reduction leads to decreases in the FOXO3-mediated oxidative stress response, Coactivator 1-α (PGC1α)-mediated ROS sequestration, and RARβ-mediated ADAM10 expression and increases in P53-mediated apoptosis, NFκB-mediated Aβ toxicity, as well as the acetylation of tau, which leads to microtubule instability and tau pathology [77]. Various Sirt1 enhancers have been identified, such as alaproclate, resveratrol, quercetin, fisetin, SRT1720, SRT1460, and A03 racemates [78,79,80,81,82,83,84].…”

Section: Novel Treatment Strategies In Admentioning

confidence: 99%

“…The Sirt1 function has a major role related to tau pathology, which is an additional risk for progression during AD. The first-in-class ApoE4 targeted therapeutic, A03, which influences Sirt1 levels might be a good candidate for preclinical trails in MCI and AD due to its excellent brain bioavailability and promising efficacy after chronic oral treatment [77].…”

Section: Novel Treatment Strategies In Admentioning

confidence: 99%

Novel Approaches for the Treatment of Alzheimer’s and Parkinson’s Disease

Bulck

Sierra-Magro

Alarcón-Gil

et al. 2019

IJMS

137

103

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Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer’s and Parkinson’s diseases. A progressive neurodegenerative process and neuroinflammation occur, and no current therapies can prevent, slow, or halt disease progression. To date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. Therefore, early diagnosis and the discovery of new targets and novel therapies are of upmost importance. Neurodegenerative diseases, like in other age-related disorders, the progression of pathology begins many years before the onset of symptoms. Many efforts in this field have led to the conclusion that exits some similar events among these diseases that can explain why the aging brain is so vulnerable to suffer neurodegenerative diseases. This article reviews the current knowledge about these diseases by summarizing the most common features of major neurodegenerative disorders, their causes and consequences, and the proposed novel therapeutic approaches.

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A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model

Cited by 26 publications

References 71 publications

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases

Presence of the apolipoprotein E-ε4 allele is associated with an increased risk of sepsis progression

Novel Approaches for the Treatment of Alzheimer’s and Parkinson’s Disease

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