Targeting γ-secretase for familial Alzheimer’s disease

Wolfe, Michael S.

doi:10.1007/s00044-021-02744-3

Cited by 5 publications

(3 citation statements)

References 66 publications

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“…Then, we used a pulldown assay to determine whether there is a direct binding interaction between PS2 and Miro2 and to identify the interacting regions. PS2 is composed of 448 amino acids and contains 7 to 9 transmembrane domains in different organelles [ 3 , 22 ]. Based on the characteristics of the transmembrane structure and the possible interaction between the extracellular domain of PS2 and Miro2, GST fusion proteins containing each of the two domains of PS2 (amino acids 1–87 and 271–361) were constructed (GST-PS2 (1–87) and GST-PS2 (271–361) , respectively).…”

Section: Resultsmentioning

confidence: 99%

Presenilin2 D439A Mutation Induces Dysfunction of Mitochondrial Fusion/Fission Dynamics and Abnormal Regulation of GTPase Activity

Gao,

Shang,

Sun

et al. 2023

Mol Neurobiol

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Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease, and approximately 10% of AD cases are early-onset familial AD (EOFAD), which is mainly linked to point mutations in genes encoding presenilins (PS1 and PS2). Mutations in PS2 are extremely rare and have not received enough attention. Recently, studies have found that Rho GTPase activity is closely related to the pathogenesis of AD. In this study, we used transcriptome sequencing in PS2 siRNA-transfected SH-SY5Y cells and found a group of differentially expressed genes (DEGs) related to the regulation of GTPase activity. Among those DEGs, the most significantly downregulated was Rho guanine nucleotide exchange factor 5 (ARHGEF5). GTPase activity in PS2 siRNA-transfected cells was significantly decreased. Then, we found that the expression of ARHGEF5 and the GTPase activity of Mitochondrial Rho GTPase 2 (Miro2) in PS2 D439A mutant SH-SY5Y cells were significantly decreased. We found for the first time that PS2 can bind to Miro2, and the PS2 D439A mutation reduced the binding between PS2 and Miro2, reduced the expression of Miro2, and resulted in an imbalance in mitochondrial fusion/fission dynamics. In conclusion, PS2 gene knockdown may participate in the pathogenesis of AD through the regulation of GTPase activity. The imbalance in mitochondrial dynamics mediated by the PS2 D439A mutation through regulation of the expression and GTPase activity of Miro2 may be a potential pathogenic mechanism of AD.

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Section: Resultsmentioning

confidence: 99%

Presenilin2 D439A Mutation Induces Dysfunction of Mitochondrial Fusion/Fission Dynamics and Abnormal Regulation of GTPase Activity

Gao,

Shang,

Sun

et al. 2023

Mol Neurobiol

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“…Although it seems that the deposit of βA could act as a trigger for pathogenesis, both pathways could act synergistically and contribute to the toxicity that leads to neurodegeneration. 73,80 Fig. 1 Metabolic association between dietetic patterns and metabolic syndrome.…”

Section: Molecular Mechanisms Of Alzheimer's Diseasementioning

confidence: 99%

Microbiota dysbiosis caused by dietetic patterns as a promoter of Alzheimer's disease through metabolic syndrome mechanisms

Navalón-Monllor,

Soriano-Romaní,

Silva

et al. 2023

Food Funct.

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“…Several carboxylic acid derivatives with improved potency and physicochemical profiles were later developed (Peng et al, 2011 ; Rogers et al, 2012 ) but were never clinically tested. In parallel, attempts were made to identify new types of gamma-secretase modulators, first identified by Neurogenetics (Cheng et al, 2004 ), but several other pharmaceutical companies followed and identified non-carboxylic acid series of compounds, with most molecules containing an aryl-imidazole moiety—the “second generation” GSMs (Xia, 2019 ; Mekala et al, 2020 ; Wolfe, 2021 ; Hur, 2022 ; Luo and Li, 2022 ). Recently, the structure of the gamma-secretase complex co-crystallized with the second-generation GSM E2012 developed by Eisai was determined (Yang et al, 2021 ).…”

Section: Gamma-secretase Modulatorsmentioning

confidence: 99%

Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease

Nordvall,

Lundkvist,

Sandin

2023

Front. Mol. Neurosci.

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Recent clinical data with three therapeutic anti-Aβ antibodies have demonstrated that removal of Aβ-amyloid plaques in early Alzheimer's disease (AD) can attenuate disease progression. This ground-breaking progress in AD medicine has validated both the amyloid cascade hypothesis and Aβ-amyloid as therapeutic targets. These results also strongly support therapeutic approaches that aim to reduce the production of amyloidogenic Aβ to prevent the formation of Aβ-pathology. One such strategy, so-called gamma-secretase modulators (GSM), has been thoroughly explored in preclinical settings but has yet to be fully tested in clinical trials. Recent scientific progress has shed new light on the role of Aβ in Alzheimer's disease and suggests that GSMs exhibit specific pharmacological features that hold great promise for the prevention and treatment of Alzheimer's disease. In this short review, we discuss the data that support why it is important to continue to progress in this class of compounds.

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Targeting γ-secretase for familial Alzheimer’s disease

Cited by 5 publications

References 66 publications

Presenilin2 D439A Mutation Induces Dysfunction of Mitochondrial Fusion/Fission Dynamics and Abnormal Regulation of GTPase Activity

Presenilin2 D439A Mutation Induces Dysfunction of Mitochondrial Fusion/Fission Dynamics and Abnormal Regulation of GTPase Activity

Microbiota dysbiosis caused by dietetic patterns as a promoter of Alzheimer's disease through metabolic syndrome mechanisms

Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease

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