Modulation of γ- and β-Secretases as Early Prevention Against Alzheimer’s Disease

Voytyuk, Iryna; Strooper, Bart De; Chávez‐Gutiérrez, Lucía

doi:10.1016/j.biopsych.2017.08.001

Cited by 56 publications

(44 citation statements)

References 111 publications

(119 reference statements)

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“…The Aβ region of APP can be cleaved by γ-secretase at different amino acids and more cleavage at amino acid 42 than at 38 and 40 is likely the most important amyloidogenic effect of presenilin [PSEN; the active site of γ-secretase] mutations that cause familial AD 33 . Hence, to investigate if culturing in BrainPhys would also modulate γ-secretase-mediated cleavage at the C-terminus of Aβ, we calculated the ratios of Aβ42/Aβ40, Aβ38/Aβ40 and Aβ38/Aβ42.…”

Section: Brainphys Increases Expression and Secretion Of Axonal Protementioning

confidence: 99%

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Accelerated neuronal and synaptic maturation by BrainPhys medium increases Aβ secretion and alters Aβ peptide ratios from iPSC-derived cortical neurons

Şatır

Nazir

Vizlin‐Hodzic

et al. 2020

Sci Rep

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one of the neuropathological hallmarks of Alzheimer's disease (AD) is cerebral deposition of amyloid plaques composed of amyloid β (Aβ) peptides and the cerebrospinal fluid concentrations of those peptides are used as a biomarker for AD. Mature induced pluripotent stem cell (ipSc)-derived cortical neurons secrete Aβ peptides in ratios comparable to those secreted to cerebrospinal fluid in human, however the protocol to achieve mature neurons is time consuming. in this study, we investigated if differentiation of neuroprogenitor cells (NPCs) in BrainPhys medium, previously reported to enhance synaptic function of neurons in culture, would accelerate neuronal maturation and, thus increase Aβ secretion as compared to the conventional neural maintenance medium. We found that npcs cultured in Brainphys displayed increased expression of markers for cortical deep-layer neurons, increased synaptic maturation and number of astroglial cells. this accelerated neuronal maturation was accompanied by increased App processing, resulting in increased secretion of Aβ peptides and an increased Aβ38 to Aβ40 and Aβ42 ratio. However, during long-term culturing in BrainPhys, nonneuronal cells appeared and eventually took over the cultures. taken together, Brainphys culturing accelerated neuronal maturation and increased Aβ secretion from ipSc-derived cortical neurons, but changed the cellular composition of the cultures. Amyloid plaques composed of aggregated amyloid beta (Aβ) peptides, predominantly species ending at amino acid 42 (Aβ42), are one of the major neuropathological hallmarks of Alzheimer's disease (AD) 1. Cerebrospinal fluid (CSF) Aβ42 concentration and the ratio of Aβ42 to Aβ40 in CSF are used as biomarkers for cerebral β-amyloidosis in AD 2. Although some forms of these Aβ peptides are believed to be molecular triggers of AD, they are also produced and secreted by cells under normal physiological conditions 3-5. Aβ peptides are generated by enzymatic cleavage of amyloid beta precursor protein (APP). Initially, APP is cleaved either by α-secretase, liberating soluble APPα (sAPPα), or by β-secretase, which releases sAPPβ. The remaining stub of APP in the latter processing pathway is then cleaved by γ-secretase to produce Aβ peptides of varying lengths 6. As an outcome of the discovery of induced pluripotent stem cells (iPSCs) 7 , functioning neurons of human origin can now be produced in vitro and these cells have also been shown by us and others to secrete measurable amounts of APP cleavage products into the cell media 8-10. Moreover, ratios of short and long Aβ peptides (ranging in size from 14 to 42 amino acids) secreted into the cell media from these mature, human iPSC-derived neurons correspond to those measured in CSF 2,11. There are many well-established, widely used protocols for cortical

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Section: Brainphys Increases Expression and Secretion Of Axonal Protementioning

confidence: 99%

“…5DII-III). This indicates that BrainPhys has an increasing effect on γ-secretase cleavage at amino acid 38 of Aβ (i.e., a cleavage pattern that could protect from amyloidosis) 33 .…”

Section: Brainphys Increases Expression and Secretion Of Axonal Protementioning

confidence: 99%

Accelerated neuronal and synaptic maturation by BrainPhys medium increases Aβ secretion and alters Aβ peptide ratios from iPSC-derived cortical neurons

Şatır

Nazir

Vizlin‐Hodzic

et al. 2020

Sci Rep

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“…The early accumulation of Aβ, in turn, triggers synaptic damage, inflammatory reaction, and pathological tau with cognitive impairment. Therapeutic development efforts have concentrated on limiting Aβ cleavage from amyloid precursor protein by secretase inhibition 1 or on promoting its clearance by active or passive immunization. 2 One alternative approach is to limit the toxic effects of accumulated Aβ rather than its level.…”

Section: Introductionmentioning

confidence: 99%

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

et al. 2019

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IMPORTANCE Oligomeric amyloid-β peptide binds to cellular prion protein on the neuronal cell surface, activating intracellular fyn kinase to mediate synaptotoxicity and tauopathy. AZD0530 is an investigational kinase inhibitor specific for the Src family, including fyn, that has been repurposed for the treatment of Alzheimer disease. OBJECTIVE To determine whether AZD0530 treatment slows the decline in cerebral metabolic rate for glucose (CMRgl) and is safe and well tolerated. DESIGN, SETTING, AND PARTICIPANTS This multicenter phase 2a randomized clinical trial enrolled participants between December 23, 2014, and November 30, 2016. Participants (n = 159) had mild Alzheimer dementia and positron emission tomography (PET) evidence of elevated levels of amyloid-β peptide. Efficacy analyses of all primary and secondary outcomes were conducted in a modified intention-to-treat population. Final analyses were conducted from February 9, 2018, to July 25, 2018. INTERVENTIONS AZD0530 (100 mg or 125 mg daily) vs placebo for 52 weeks. MAIN OUTCOMES AND MEASURES Primary outcome was the reduction in relative CMRgl, as measured by 18 F-fluorodeoxyglucose (18 F-FDG) PET, at 52 weeks in an Alzheimer disease-associated prespecified statistical region of interest. Secondary end points included change in cognition, function, and other biomarkers. RESULTS Among the 159 participants, 79 were randomized to receive AZD0530 and 80 to receive placebo. Of the 159 participants, 87 (54.7%) were male, with a mean (SD) age of 71.0 (7.7) years. Based on a week-2 plasma drug level (target = 180 ng/mL; 30nM free), 15 participants (19.2%) had their AZD0530 dose escalated from 100 mg to 125 mg. Mean plasma levels from weeks 13 to 52 were 220 ng/mL and 36nM free. More participants discontinued treatment with AZD0530 than with placebo (21 vs 11), most commonly because of adverse events. The most frequent adverse events were gastrointestinal disorders (primarily diarrhea), which occurred in 38 participants (48.1%) who received AZD0530 and in 23 (28.8%) who received placebo. In the primary outcome, the treatment groups did not differ in 52-week decline in relative CMRgl (mean difference: −0.006 units/y; 95% CI, −0.017 to 0.006; P = .34). The treatment groups also did not differ in the rate of change in Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living, Clinical Dementia Rating, Neuropsychiatric Inventory, or Mini-Mental State Examination scores. Secondary volumetric magnetic resonance imaging analyses revealed no treatment effect on total brain or ventricular volume but did show trends for slowing the reduction in hippocampal volume and entorhinal thickness. CONCLUSIONS AND RELEVANCE Statistically significant effects of AZD0530 treatment were not found on relative CMRgl reduction in an Alzheimer disease-associated region of interest or on secondary clinical or biomarker measures.

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“…The optimal time point for a treatment with BACE1 inhibitors is a crucial issue that possibly explains some of the previous failures. The advances in technological diagnostic tools allowing better identification of patients at risk of developing AD, will enable clinical trials at preclinical stage when BACE1 inhibitors are expected to have the largest impact on amyloid plaques (Voytyuk et al, 2018 ).…”

Section: Future Perspectivesmentioning

confidence: 99%

Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

et al. 2018

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Alzheimer's disease (AD) is a severe neurodegenerative disorder and the most common type of dementia in the elderly. The clinical symptoms of AD include a progressive loss of memory and impairment of cognitive functions interfering with daily life activities. The main neuropathological features consist in extracellular amyloid-β (Aβ) plaque deposition and intracellular Neurofibrillary tangles (NFTs) of hyperphosphorylated Tau. Understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of neuroprotective agents able to prevent disease progression. According to the “Amyloid Cascade Hypothesis” the critical molecular event in the pathogenesis of AD is the accumulation of Aβ neurotoxic oligomers. Since the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (beta-site APP cleaving enzyme 1, BACE1) is the rate-limiting step in the production of Aβ, this enzyme is considered a major therapeutic target and BACE1 inhibitors have the potential to be disease-modifying drugs for AD treatment. Therefore, intensive efforts to discover and develop inhibitors that can reach the brain and effectively inhibit BACE1 have been pursued by several groups worldwide. The aim of this review is to highlight the progress in the discovery of potent and selective small molecule BACE1 inhibitors over the past decade.

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Modulation of γ- and β-Secretases as Early Prevention Against Alzheimer’s Disease

Cited by 56 publications

References 111 publications

Accelerated neuronal and synaptic maturation by BrainPhys medium increases Aβ secretion and alters Aβ peptide ratios from iPSC-derived cortical neurons

Accelerated neuronal and synaptic maturation by BrainPhys medium increases Aβ secretion and alters Aβ peptide ratios from iPSC-derived cortical neurons

Effect of AZD0530 on Cerebral Metabolic Decline in Alzheimer Disease

Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

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