BACE1: a key regulator in Alzheimer’s disease progression and current development of its inhibitors

2021 ◽  
Vol 19 ◽  
Author(s):  
Smith Patel ◽  
Ankush Vardhaman Bansoad ◽  
Rakesh Singh ◽  
Gopal L. Khatik
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Status ◽  
Current Development ◽  
Quality Work ◽  
Rate Limiting Step ◽  
Disease Modifying Treatment ◽  
Rate Limiting

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease where no specific disease-modifying treatment is currently available. β-secretase (BACE1) is considered the potential and rationale target because it is involved in the rate-limiting step, which produces toxic Aβ42 peptides leading to deposits in the form of amyloid plaques extracellularly leading to AD. Objective: The role and implications of BACE1 and its inhibitors in the management of AD are discussed. Methods: We have searched and collected the relevant quality work from PubMed using the following keywords “BACE1”, BACE2”, “inhibitors”, and “Alzheimer’s disease”. In addition, we included the work which discusses the role of BACE1 in AD and the recent work on its inhibitors. Results: In this review, we have discussed the importance of BACE1 in regulating AD progression and the current development of BACE1 inhibitors. However, the development of a BACE1 inhibitor is very challenging due to the large active site of BACE1. Nevertheless, some of the BACE1 inhibitors have managed to enter advanced phases of clinical trials, such as MK-8931 (Verubecestat), E2609 (Elenbecestat), AZD3293 (Lanabecestat), and JNJ-54861911 (Atabecestat). This review also sheds light on the prospect of BACE1 inhibitors as the most effective therapeutic approach in delaying or preventing AD progression. Conclusion: BACE1 is involved in the progression of AD. The current ongoing or failed clinical trials may help understand the role of BACE1 inhibition in regulating the Aβ load and cognitive status of AD patients.

The role of EEG in clinical trials on Alzheimer's disease

2014 ◽  
Vol 35 ◽  
pp. S23
Author(s):  
Ilse van Straaten ◽  
P. Scheltens ◽  
C.J. Stam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials

scholarly journals Kaleidoscope

2014 ◽  
Vol 205 (4) ◽  
pp. 334-335
Author(s):  
Derek K. Tracy ◽  
Dan W. Joyce ◽  
Sukhwinder S. Shergill
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variant ◽  
Age At Onset ◽  
Epidemiological Data ◽  
Gene Encoding ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Impact ◽  
Rate Limiting

It cannot have escaped our readers' notice that there has been a public increase in the awareness of the impact of dementia on people's lives: politicians have raised concerns about a dementia ‘time bomb’ as a greater number of people live to an older age; and even the 2013 G8 summit declared1 that there was a need for international initiatives to tackle this illness. The inevitable call for more research is underscored by the lack of any new licenced medications for Alzheimer's disease since 2002. There has been much interest in a putative role for statins – which inhibit the HMGCR enzyme, the rate-limiting step in cholesterol production – as retrospective epidemiological data have shown that they can reduce the risk of developing Alzheimer's disease by up to 70%; but, frustratingly, administration of these drugs to those with the illness appears to produce little benefit. Recent data have now shown that the gene encoding this HMGCR enzyme is a potent modifier for the age at onset and rate of conversion from mild cognitive impairment to Alzheimer's disease.2 Indeed, this work would indicate that its G-negative allele is second only to APOE2 as the most common and important protective genetic variant for spontaneous Alzheimer's disease.

Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions

2010 ◽  
Vol 391 (8) ◽  
Author(s):  
David W. Klaver ◽  
Matthew C.J. Wilce ◽  
Hao Cui ◽  
Amos C. Hung ◽  
Robert Gasperini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Active Site ◽  
Translational Regulation ◽  
Precursor Protein ◽  
Future Directions ◽  
Rate Limiting Step ◽  
Β Amyloid ◽  
Rate Limiting ◽  
Major Target

Abstract Alzheimer's disease (AD) is characterized by the extracellular deposition of the β-amyloid protein (Aβ). Aβ is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by β-secretase and γ-secretase liberates Aβ from APP. The aspartyl protease BACE1 (β-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Aβ, and as such it is considered to be a major target for drug development in Alzheimer's disease. However, the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood-brain barrier. This review focuses on the structure BACE1, current therapeutic strategies based on developing active-site inhibitors, and new approaches to therapy involving targeting the expression or post-translational regulation of BACE1.

scholarly journals P1-387: Mild to moderate Alzheimer's disease (AD) clinical trials: The role of hippocampal atrophy as an inclusion criterion

2010 ◽  
Vol 6 ◽  
pp. S285-S286
Author(s):  
Robert Risinger ◽  
Robert M Berman ◽  
Vlad Coric ◽  
Jian Han ◽  
Stephen Kaplita ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Hippocampal Atrophy

scholarly journals MicroRNAs and Alzheimer's Disease Mouse Models: Current Insights and Future Research Avenues

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Charlotte Delay ◽  
Sébastien S. Hébert
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Models ◽  
Mouse Models ◽  
Future Research ◽  
Neuronal Function ◽  
Key Genes

Evidence from clinical trials as well as from studies performed in animal models suggest that both amyloid and tau pathologies function in concert with other factors to cause the severe neurodegeneration and dementia in Alzheimer’s disease (AD) patients. Accumulating data in the literature suggest that microRNAs (miRNAs) could be such factors. These conserved, small nonprotein-coding RNAs are essential for neuronal function and survival and have been implicated in the regulation of key genes involved in genetic and sporadic AD. The study of miRNA changes in AD mouse models provides an appealing approach to address the cause-consequence relationship between miRNA dysfunction and AD pathology in humans. Mouse models also provide attractive tools to validate miRNA targetsin vivoand provide unique platforms to study the role of specific miRNA-dependent gene pathways in disease. Finally, mouse models may be exploited for miRNA diagnostics in the fight against AD.

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