The Swedish dilemma - the almost exclusive use of APPswe-based mouse models impedes adequate evaluation of alternative β-secretases

Armbrust, Fred; Bickenbach, Kira; Marengo, Liana; Pietrzik, Claus U.; Becker‐Pauly, Christoph

doi:10.1016/j.bbamcr.2021.119164

Cited by 16 publications

(19 citation statements)

References 153 publications

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“…The presented mechanisms support proposals that the majority of uncertainties and inconstancies in studies of γ-secretase can be eliminated by controlling saturation of γ-secretase with its substrate [6,9,11-13,17,18,88]. All studies of γ-secretase activity can have a competition between substrates binding to γ-secretase (Fig.…”

Section: Discussionsupporting

confidence: 78%

“…The measurements at different saturations require extra efforts and costs. However, such measurements can give consistent results and sustained progress in enzyme-based, cell-based and computational studies [7-11,13,40,53,54,88].…”

Section: Discussionmentioning

confidence: 98%

“…2). In cell-based studies dimerization of C99-βCTF-APP molecules is controlled by cell physiology, and could get out of control in cells that have unphysiological overexpression of C99-βCTF-APP molecules [6,88]. In enzyme-based studies dimerization between C99-βCTF-APP molecules can be minimized by starting the assays with the substrates that come immediately after elution from the affinity column by low pH [10].…”

Section: Discussionmentioning

confidence: 99%

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Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

Svedružić

Šendula-Jengić

Ostojić

2022

Preprint

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Significance: pathogenic changes in γ-secretase activity, and its response to different drugs, can be greatly affected by changes in saturation of γ-secretase with its substrate. The molecular mechanism is unclear. Results: multiscale molecular dynamics studies show that saturation of γ-secretase with its substrate can result in parallel binding of different substrate molecules at the docking site and the active site. C-terminal domain of the second substrate can bind at cytosolic end of presenilin subunit while γ-secretase is still processing its first substrate. Such interactions can disrupt dynamic presenilin structures that regulate proteolytic steps. Similar disruptions in dynamic presenilin structures can be produced by different drugs and by different disease-causing mutations. Thus, the presented two-substrate mechanism, can explain toxic inhibition of γ-secretase activity and toxic increase in production of the longer, more hydrophobic, Aβ-proteins. Toxic aggregation between N-terminal domains of the two substrates is controlled by nicastrin ectodomain. Such aggregation is more likely to happen with C99-βCTF-APP than with C83-αCTF-APP substrate, which can explain, why β-secretase path is more pathogenic than α-secretase path. The binding of C99-βCTF-APP substrate to γ-secretase can be controlled by substrate-channeling between nicastrin ectodomain and β-secretase. Conclusions: The presented two-substrate mechanism can explain why different studies consistently show that increase in saturation of γ-secretase with its substrate can support pathogenic changes in different sporadic and familiar cases of the disease. Future drug-development strategies can target different physiological mechanisms that control the balance between cellular levels of γ-secretase activity and the total amyloid metabolism.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

Svedružić

Šendula-Jengić

Ostojić

2022

Preprint

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“…In addition, the decreased levels of γ-aminobutyric acid (GABA) and Glu reflected the restricted development of Parkinson’s disease, while the increased levels of GAP-43 and NF-H reflected the promotion of neuronal growth and plasticity [ 47 ]. Alzheimer’s disease is another common neurodegenerative disease, and abnormal aggregation of β-amyloid is often considered as being the main cause of Alzheimer’s disease development [ 95 ]. Treatment with DAPs extracted in three different ways in the Alzheimer’s disease model of C. elegans significantly improved motility and inhibited β-amyloid deposition in C. elegans , with the DAPs extracted using combined pepsin and trypsin hydrolysis having the best efficacy [ 43 ].…”

Section: Biological Functions Of Dapsmentioning

confidence: 99%

Health Effects of Peptides Extracted from Deer Antler

Xia

Liu²,

Jiao

et al. 2022

Nutrients

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Deer antler is widely used as a nutraceutical in Asian countries. In the past decades, deer antler peptides (DAPs) have received considerable attention because of their various biological properties such as antioxidant, anti-inflammatory, anti-bone damage, anti-neurological disease, anti-tumor and immunomodulatory properties. This review describes the production methods of DAPs and the recent progress of research on DAPs, focusing on the physiological functions and their regulatory mechanisms.

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“…Similarly, the popular 5xFAD mouse model expresses human APP with a non-natural combination of the mutations K670N/M671L (Swedish), I716V (Florida), and V717I (London), and human Presenilin-1 bearing the mutations M146L and L286V [ 91 ]. Thus, in comparison to the average human population, these mouse models likely have a bias in APP processing [ 92 ]. Nonetheless, humans and transgenic mice share two competing principal pathways for APP processing (see Figure 3 ).…”

Section: Processes That Lead To the Generation Of Non-canonical Aβ Va...mentioning

confidence: 99%

The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease

Busch

Eggert²,

Bufe

2022

Cells

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Recent advances have placed the pro-inflammatory activity of amyloid β (Aβ) on microglia cells as the focus of research on Alzheimer’s Disease (AD). Researchers are confronted with an astonishing spectrum of over 100 different Aβ variants with variable length and chemical modifications. With the exception of Aβ1-42 and Aβ1-40, the biological significance of most peptides for AD is as yet insufficiently understood. We therefore aim to provide a comprehensive overview of the contributions of these neglected Aβ variants to microglia activation. First, the impact of Aβ receptors, signaling cascades, scavenger mechanisms, and genetic variations on the physiological responses towards various Aβ species is described. Furthermore, we discuss the importance of different types of amyloid precursor protein processing for the generation of these Aβ variants in microglia, astrocytes, oligodendrocytes, and neurons, and highlight how alterations in secondary structures and oligomerization affect Aβ neurotoxicity. In sum, the data indicate that gene polymorphisms in Aβ-driven signaling pathways in combination with the production and activity of different Aβ variants might be crucial factors for the initiation and progression of different forms of AD. A deeper assessment of their interplay with glial cells may pave the way towards novel therapeutic strategies for individualized medicine.

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The Swedish dilemma - the almost exclusive use of APPswe-based mouse models impedes adequate evaluation of alternative β-secretases

Cited by 16 publications

References 153 publications

Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

Health Effects of Peptides Extracted from Deer Antler

The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease

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