Identification of new Presenilin-1 phosphosites: implication for γ-secretase activity and Aβ production

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

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P4-296 Fatty acids increase presenilin 1 levels and gamma-secretase activity in PSWT-1 cells

Neurobiology of Aging ◽

10.1016/s0197-4580(04)81854-2 ◽

2004 ◽

Vol 25 ◽

pp. S559

Author(s):

Neil S. Shachter ◽

Yanzhu Liu ◽

Lin Yang ◽

Karin Conde-Knape ◽

Dirk Beher ◽

...

Keyword(s):

Fatty Acids ◽

Presenilin 1 ◽

Gamma Secretase ◽

Secretase Activity

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Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity

Nature ◽

10.1038/19077 ◽

1999 ◽

Vol 398 (6727) ◽

pp. 513-517 ◽

Cited By ~ 1336

Author(s):

Michael S. Wolfe ◽

Weiming Xia ◽

Beth L. Ostaszewski ◽

Thekla S. Diehl ◽

W. Taylor Kimberly ◽

...

Keyword(s):

Presenilin 1 ◽

Secretase Activity

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Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane

Journal of Biological Chemistry ◽

10.1074/jbc.m304009200 ◽

2003 ◽

Vol 278 (29) ◽

pp. 26687-26694 ◽

Cited By ~ 192

Author(s):

Stephen H. Pasternak ◽

Richard D. Bagshaw ◽

Marianne Guiral ◽

Sunqu Zhang ◽

Cameron A. Ackerley ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Lysosomal Membrane ◽

Precursor Protein ◽

Presenilin 1 ◽

Secretase Activity

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Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice

Neurochemical Research ◽

10.1007/s11064-015-1807-7 ◽

2015 ◽

Vol 41 (5) ◽

pp. 1145-1159 ◽

Cited By ~ 1

Author(s):

Feng-li Zhao ◽

Pei-feng Qiao ◽

Ning Yan ◽

Dan Gao ◽

Meng-jie Liu ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Transgenic Mice ◽

Secretase Activity ◽

Aβ Production

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The Transmembrane Aspartates in Presenilin 1 and 2 Are Obligatory for γ-Secretase Activity and Amyloid β-Protein Generation

Journal of Biological Chemistry ◽

10.1074/jbc.275.5.3173 ◽

2000 ◽

Vol 275 (5) ◽

pp. 3173-3178 ◽

Cited By ~ 178

Author(s):

W. Taylor Kimberly ◽

Weiming Xia ◽

Talat Rahmati ◽

Michael S. Wolfe ◽

Dennis J. Selkoe

Keyword(s):

Amyloid Β ◽

Presenilin 1 ◽

Amyloid Β Protein ◽

Β Protein ◽

Secretase Activity

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P4-051: The biological effects of R278I-Presenilin-1 familial mutation on γ-secretase activity and amyloid pathology

Alzheimer s & Dementia ◽

10.1016/j.jalz.2009.04.820 ◽

2009 ◽

Vol 5 (4S_Part_15) ◽

pp. P446-P446

Author(s):

Takashi Saito ◽

Takahiro Suemoto ◽

Naomi Mihira ◽

Yukio Matsuba ◽

Jiro Takano ◽

...

Keyword(s):

Biological Effects ◽

Presenilin 1 ◽

Amyloid Pathology ◽

Secretase Activity

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GSAP modulates γ-secretase specificity by inducing conformational change in PS1

10.1101/461061 ◽

2018 ◽

Author(s):

Eitan Wong ◽

George P. Liao ◽

Jerry Chang ◽

Peng Xu ◽

Yue-Ming Li ◽

...

Keyword(s):

Conformational Change ◽

Active Site ◽

Cultured Cells ◽

Cross Linking ◽

Secretase Activity ◽

Aβ Production ◽

Insight Into ◽

Double Cross

AbstractThe mechanism by which GSAP (γ-secretase activating protein) regulates γ-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces γ-secretase activity for Aβ production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of γ-secretase. Furthermore, using an active site directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of PS1-NTF and PS1-CTF, a region containing the active site of γ-secretase. This work offers insight into how GSAP regulates γ-secretase specificity.

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Evaluation of Toxic Amyloid β42 Oligomers in Rat Primary Cerebral Cortex Cells and Human iPS-derived Neurons Treated with 10-Me-Aplog-1, a New PKC Activator

International Journal of Molecular Sciences ◽

10.3390/ijms21041179 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1179

Author(s):

Kazuma Murakami ◽

Mayuko Yoshimura ◽

Shota Nakagawa ◽

Toshiaki Kume ◽

Takayuki Kondo ◽

...

Keyword(s):

Cerebral Cortex ◽

Total Synthesis ◽

Bryostatin 1 ◽

Oligomer Formation ◽

Promising Strategy ◽

Secretase Activity ◽

Drug Lead ◽

Protein Kinase Cα ◽

Aβ Production ◽

Ad Therapy

Amyloid β42 (Aβ42), a causative agent of Alzheimer’s disease (AD), is derived extracellularly from Aβ precursor protein (APP) following the latter’s cleavage by β-secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing Aβ production. Since Aβ42 oligomer formation causes potent neurotoxicity, APP modulation by PKC ligands is a promising strategy for AD treatment. Although bryostatin-1 (bryo-1) is a leading compound for this strategy, its limited natural availability and the difficulty of its total synthesis impedes further research. To address this limitation, Irie and colleagues have developed a new PKC activator with few side effects, 10-Me-Aplog-1, (1), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKCε-dependent Aβ-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known β-secretase stabilizer, was reduced by treatment with 1. Notably, 1 prevented the formation of intracellular toxic oligomers. Furthermore, 1 suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that 1 was not neurotoxic toward either cell line, these findings suggest that 1 is a potential drug lead for AD therapy.

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