BACE inhibitors as potential therapeutics for Alzheimer's disease Abstract Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD.
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What are BACE1 inhibitors for Alzheimer's disease?
Key Points β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are potential disease-modifying drugs for Alzheimer’s disease (AD) treatment as they prevent the production of synaptotoxic amyloid-β (Aβ).
What is the difference between BACE1 and BACE2 inhibitors?
The practical BACE1 inhibitors should be small in size and cross the blood–brain barrier easily as BACE1 is richly expressed in the brain, predominantly in neurons, and is readily detected in presynaptic hippocampal mossy fiber terminals, whereas its homolog BACE2 (64% amino acid sequence homology) is more sparsely expressed.
Is there an optimal time point for treatment with BACE1 inhibitors?
Emerging evidences suggest that the optimal timing for treatment with BACE1 inhibitors should be as early as possible. The optimal time point for a treatment with BACE1 inhibitors is a crucial issue that possibly explains some of the previous failures.
Is plasma beta-secretase (BACE1) activity a biomarker for Alzheimer's disease?
Wu G, et al. Characterization of plasma beta-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer’s disease. J Neurosci Res. 2012;90(12):2247–58. [PubMed] [Google Scholar] 122. Vassar R BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther. 2014;6(9):89.
What is a BACE inhibitor?
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are potential disease-modifying drugs for Alzheimer's disease (AD) treatment as they prevent the production of synaptotoxic amyloid-β (Aβ).
How do gamma secretase inhibitors work?
Gamma secretase inhibitors (GSIs) are a class of drugs that gained attention during the past decade in cancer treatment. The use of GSIs for cancers is primarily based on the premise that GSIs act by inhibiting the cleavage of γ-secretase, which result in blocking Notch 1 signaling [272].
What are the beta secretase inhibitors?
BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes.
What does BACE1 stand for?
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons.
Why would a chemical inhibitor of γ secretase be potentially useful for treating Alzheimer's disease?
Gamma secretase inhibitors (GSIs) have long been investigated for their potential as Alzheimer's disease (AD) treatments due to their ability to block secretion of amyloid β-peptide, the precursor of amyloid plaques associated with AD.
How can Secretases lead to worsening of Alzheimer's disease?
Inhibitors of γ-secretase have failed in clinical trials, causing toxicities resulting from blocking the proteolysis of another substrate and cognitive worsening that may be due to elevation of APP substrates.
What is adult BACE1?
Abstract. BACE1 initiates the generation of the β-amyloid peptide, which likely causes Alzheimer's disease (AD) when accumulated abnormally. BACE1 inhibitory drugs are currently being developed to treat AD patients.
What is BACE1 gene?
BACE1 (Beta-Secretase 1) is a Protein Coding gene. Diseases associated with BACE1 include Alzheimer Disease, Familial, 1 and Myositis. Among its related pathways are Alzheimers Disease Pathway and RNA Polymerase I Promoter Opening.
What does BACE1 enzyme do?
Given that BACE1 is the initiating enzyme in Aβ generation, and putatively rate-limiting, it is considered a prime drug target for lowering cerebral Aβ levels in the treatment and/or prevention of AD.
What is BACE protein?
The β-secretase, β-site amyloid precursor protein cleaving enzyme (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating Aβ generation. Thus, BACE is a prime drug target for the therapeutic inhibition of Aβ production in AD. Since its discovery 10 years ago, much has been learned about BACE.
Where is BACE1 found?
The levels of BACE1 mRNA are highest in brain and pancreas and are significantly lower in most other tissues. Moreover, BACE1 mRNA is highly expressed in neurons but little is found in resting glial cells of the brain, as expected for β-secretase. The protein is abundant in both normal human and AD brain [19, 28].
Does AD prevent disease progression?
Aggravating this situation, drugs that are currently US Food and Drug Administration (FDA)-approved for AD treatment do not prevent or delay disease progression. T …. Alzheimer's disease (AD), the most common cause of age-dependent dementia, is one of the most significant healthcare problems worldwide. Aggravating this situation, drugs that are ...
Is Bace1 a pharmacological inhibitor?
Therefore, pharmacological inhibition of BACE1 is being intensively pursued as a therapeutic approach to treat AD patients. Recent setbacks in clinical trials with BACE1 inhibitors have highlighted the critical importance of understanding how to properly inhibit BACE1 to treat AD patients.