The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice

Dekeryte, Ruta; Franklin, Zara J.; Hull, Claire; Croce, Lorenzo; Kamli-Salino, Sarah; Helk, Oliver; Hoffmann, Philip; Yang, Zhihui; Riedel, Gernot; Delibegović, Mirela; Platt, Bettina

doi:10.1016/j.bbadis.2021.166149

Cited by 11 publications

(6 citation statements)

References 27 publications

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“…LY2886721 is a potent and selective active site inhibitor of β-secretase (BACE1,2) without inhibition of other proteases such as cathepsin D, pepsin and renin [22,33]. LY2886721 demonstrates an effective dose-dependent decrease in the level of Aβ and sAPPβ in a different experimental models: in HEK293 cells with the APP751 mutation; in primary cortical neurons of PDAPP-mutated mice [52] ; in vivo animal models (3-30 mg/kg PDAPP mice, 1.5 mg/kg beagle dogs; orally) [22,[52][53][54]. In transgenic mice, doses of 3-30 mg/kg reduced Aβ levels by 20-65%.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Precursor Protein, Alpha-, Beta- and Gamma-Secretases Expression in Penumbra Cells after Photothrombotic Stroke. Evaluation of the Neuroprotective Effect of Secretase Inhibitors

Sharifulina¹,

Guzenko²,

Logvinov³

et al. 2022

Preprint

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Photothrombotic stroke (PTS) stimulates the level of N- and C-terminal fragments of Amyloid precursor protein (APP) growth in the cytoplasm of ischemic penumbra cells not earlier but at 24 hours. Here we have shown that APP fragments are visualized in thin unmyelinated fibers of neurons, in containing mitochondria large fibers and in synapses but absent in the nuclei. At 24 hours after PTS, some elements of the destroyed tissue accumulated a significant amount of APP protein. The level of ADAM10 α-secretase decreased on the first day after PTS in the rat brain cortex and ADAM-10 co-localized with the lipid raft marker caveolin-1. PTS caused no changes in the level of β-secretase BACE1 either on the first day after PTS or in the early recovery period. The expression of proteins of the γ-secretase complex: presenilin-1 and nicastrin increased in astrocytes, but not in penumbra neurons after PTS. The β-secretase inhibitor LY2886721 did not affect the infarct size of the mouse cerebral cortex and the level of apoptosis of cells in the perifocal region after PTS. Whereas the inhibitor of γ-secretase DAPT reduced the expression of glial fibrillary acidic protein (GFAP) in astrocytes, prevented the growth of apoptosis of mouse cerebral cortex cells reducing the infarct volume on the 7th and 14th days after PTS. DAPT may be considered as a drug for stroke therapy.

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Section: Discussionmentioning

confidence: 99%

Amyloid Precursor Protein, Alpha-, Beta- and Gamma-Secretases Expression in Penumbra Cells after Photothrombotic Stroke. Evaluation of the Neuroprotective Effect of Secretase Inhibitors

Sharifulina¹,

Guzenko²,

Logvinov³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…LY2886721 demonstrates an effective dose-dependent decrease in the level of Aβ and sAPPβ in different experimental models: in HEK293 cells with the APP751 mutation; in primary cortical neurons of PDAPP-mutated mice [ 72 ]; in vivo animal models (3–30 mg/kg PDAPP mice, 1.5 mg/kg beagle dogs; orally) [ 22 , 52 , 53 , 54 ]. In transgenic mice, doses of 3–30 mg/kg reduced Aβ levels by 20–65%.…”

Section: Discussionmentioning

confidence: 99%

Expression of Amyloid Precursor Protein, Caveolin-1, Alpha-, Beta-, and Gamma-Secretases in Penumbra Cells after Photothrombotic Stroke and Evaluation of Neuroprotective Effect of Secretase and Caveolin-1 Inhibitors

et al. 2022

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Our studies reveal changes in the expression of the main participants in the processing of amyloid precursor protein (APP) in neurons and astrocytes after photothrombotic stroke (PTS). Here we show the increase in the level of N- and C-terminal fragments of APP in the cytoplasm of ischemic penumbra cells at 24 h after PTS and their co-immunoprecipitation with caveolin-1. The ADAM10 α-secretase level decreased in the rat brain cortex on the first day after PTS. Levels of γ-secretase complex proteins presenilin-1 and nicastrin were increased in astrocytes, but not in neurons, in the penumbra after PTS. Inhibitory analysis showed that these changes lead to neuronal death and activation of astrocytes in the early recovery period after PTS. The caveolin-1 inhibitor daidzein shifted APP processing towards Aβ synthesis, which caused astroglial activation. γ-secretase inhibitor DAPT down-regulated glial fibrillary acidic protein (GFAP) in astrocytes, prevented mouse cerebral cortex cells from PTS-induced apoptosis, and reduced the infarction volume. Thus, new generation γ-secretase inhibitors may be considered as potential agents for the treatment of stroke.

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“…injection of glucose solution (20% w/v glucose) in the dose of 2mg/g body weight (b.w.). Tail blood glucose was measured at the times 15-, 30-, 60-, and 90-minutes post-injection, as described (75).…”

Section: Methodsmentioning

confidence: 99%

Effects of age and dietary methionine restriction on cognitive and behavioural phenotypes in the rTg4510 model of frontotemporal dementia

Matos,

Sil,

Riedel

et al. 2024

Preprint

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Metabolic disorders such as diabetes and obesity are linked to neurodegenerative diseases, with evidence of decreased brain glucose metabolism and insulin resistance in patients with dementia. Given the rising prevalence of age-related diseases, lifestyle adjustments and nutritional interventions are gaining interest. Dietary methionine restriction (MR) is a nutritional intervention that enhances insulin sensitivity and delays ageing-associated metabolic alterations. Since the potential impact of MR on neurodegenerative diseases like dementia is not fully understood, we here examined the metabolic and behavioural phenotypes of a murine tauopathy model (rTg4510), which overexpresses human P301L mutated tau, and assessed the impact of an 8-week dietary MR. The rTg4510 mice and wild type (WT) littermates were assessed at 6 and 12 months of age. While rTg4510 mice displayed progressive behavioural and motor impairments at 6 and 12 months of age, MR led to significant benefits in the aged 12-month-old cohort, improving motor coordination and learning, short-term memory, and social recognition. These effects were accompanied by increased glycolysis in the hippocampus and higher FGF21 levels in the cortex. These benefits occurred in the absence of alterations in glucose metabolism/adiposity in this model. Overall, our results support the positive impact of MR on rTg4510 mice, suggesting this as a potential therapeutic intervention to delay and/or improve the progression in tau-related disease.

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The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice

Cited by 11 publications

References 27 publications

Amyloid Precursor Protein, Alpha-, Beta- and Gamma-Secretases Expression in Penumbra Cells after Photothrombotic Stroke. Evaluation of the Neuroprotective Effect of Secretase Inhibitors

Amyloid Precursor Protein, Alpha-, Beta- and Gamma-Secretases Expression in Penumbra Cells after Photothrombotic Stroke. Evaluation of the Neuroprotective Effect of Secretase Inhibitors

Expression of Amyloid Precursor Protein, Caveolin-1, Alpha-, Beta-, and Gamma-Secretases in Penumbra Cells after Photothrombotic Stroke and Evaluation of Neuroprotective Effect of Secretase and Caveolin-1 Inhibitors

Effects of age and dietary methionine restriction on cognitive and behavioural phenotypes in the rTg4510 model of frontotemporal dementia

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