Memapsin 2 (β-secretase) as a therapeutic target

2002 ◽  
Vol 30 (4) ◽  
pp. 530-534 ◽  
Author(s):  
L. Hong ◽  
R. T. Turner ◽  
G. Koelsch ◽  
A. K. Ghosh ◽  
J. Tang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Amyloid Β ◽  
Design Strategy ◽  
Precursor Protein ◽  
Inhibitor Design ◽  
Memapsin 2

As β-secretase, memapsin 2 cleaves amyloid-β precursor protein, which leads ultimately to the onset of Alzheimer's disease. As such, memapsin 2 is an excellent target of inhibitor drugs for the treatment of this disease. Here we describe the tools for memapsin 2 inhibitor design that have been developed and results from the structure-based inhibitor design. Strategy for the design of memapsin 2 inhibitors with pharmaceutical potential is also discussed.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

2019 ◽  
Author(s):  
Mingeun Kim ◽  
Juhye Kang ◽  
Misun Lee ◽  
Jiyeon Han ◽  
Geewoo Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Amyloid Β ◽  
Design Strategy ◽  
Design Approach ◽  
Metal Free

We report a minimalistic redox-based design strategy for engineering compact molecules based on the simplest aromatic framework, benzene, with multi-reactivity against free radicals, metal-free amyloid-β, and metal-bound amyloid-β, implicated in the most common form of dementia, Alzheimer’s disease.

scholarly journals Effects of Huanglian-Jie-Du-Tang and Its Modified Formula on the Modulation of Amyloid-β Precursor Protein Processing in Alzheimer's Disease Models

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e92954 ◽  
Author(s):  
Siva Sundara Kumar Durairajan ◽  
Ying-Yu Huang ◽  
Pui-Yee Yuen ◽  
Lei-Lei Chen ◽  
Ka-Yan Kwok ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Protein Processing ◽  
Precursor Protein ◽  
Disease Models ◽  
Modified Formula

A Numerical Study of Sensitivity Coefficients for a Model of Amyloid Precursor Protein and Tubulin-Associated Unit Protein Transport and Agglomeration in Neurons at the Onset of Alzheimer's Disease

2019 ◽  
Vol 141 (3) ◽  
Author(s):  
I. A. Kuznetsov ◽  
A. V. Kuznetsov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Tau Protein ◽  
Protein Transport ◽  
Numerical Study ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Model Parameters ◽  
In The Beginning

Modeling of intracellular processes occurring during the development of Alzheimer's disease (AD) can be instrumental in understanding the disease and can potentially contribute to finding treatments for the disease. The model of intracellular processes in AD, which we previously developed, contains a large number of parameters. To distinguish between more important and less important parameters, we performed a local sensitivity analysis of this model around the values of parameters that give the best fit with published experimental results. We show that the influence of model parameters on the total concentrations of amyloid precursor protein (APP) and tubulin-associated unit (tau) protein in the axon is reciprocal to the influence of the same parameters on the average velocities of the same proteins during their transport in the axon. The results of our analysis also suggest that in the beginning of AD the aggregation of amyloid-β and misfolded tau protein have little effect on transport of APP and tau in the axon, which suggests that early damage in AD may be reversible.

scholarly journals MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation

Brain ◽  
2018 ◽  
Vol 142 (1) ◽  
pp. 176-192 ◽  
Author(s):  
Bing-Lin Zhu ◽  
Yan Long ◽  
Wei Luo ◽  
Zhen Yan ◽  
Yu-Jie Lai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Translation Initiation Factor ◽  
Precursor Protein ◽  
Initiation Factor ◽  
Luciferase Reporter ◽  
Protein Levels ◽  
Model Of Alzheimer’S Disease

AbstractMMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer’s disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (β-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5′ untranslated region (5′UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5′UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer’s disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-β precursor protein processing, amyloid-β load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer’s disease, via the translational regulation of BACE1.

Abnormal platelet amyloid‐β precursor protein metabolism in SAMP8 mice: Evidence for peripheral marker in Alzheimer's disease

2019 ◽  
Vol 234 (12) ◽  
pp. 23528-23536 ◽  
Author(s):  
Lizhi Chen ◽  
Shicheng Xu ◽  
Tong Wu ◽  
Yijia Shao ◽  
Li Luo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Metabolism ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Samp8 Mice

Absence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases

2013 ◽  
Vol 34 (10) ◽  
pp. 2441.e7-2441.e8 ◽  
Author(s):  
Simon Kang Seng Ting ◽  
Mei-Sian Chong ◽  
Nagaendran Kandiah ◽  
Shahul Hameed ◽  
Louis Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurological Diseases ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Protein Variant

Genetic variability at the amyloid-β precursor protein locus may contribute to the risk of late-onset Alzheimer's disease

1999 ◽  
Vol 269 (2) ◽  
pp. 67-70 ◽  
Author(s):  
Fabienne Wavrant-De Vrièze ◽  
Richard Crook ◽  
Peter Holmans ◽  
Patrick Kehoe ◽  
Michael J. Owen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variability ◽  
Late Onset ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Protein Locus
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