Amyloid Targeting Therapies Study

Background of Amyloid Targeting Therapies Study

The accumulation of amyloid-β (Aβ) peptides is the main cause of neurodegenerative Alzheimer's disease (AD). Aβ usually starts to accumulate in the brain 15-20 years before clinical manifestations, resulting from the defective function of extracellular amyloid clearance. Presently, there is no effective therapy for AD treatment. Clinical trials for drugs targeting γ-secretase inhibitors, β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors, and Aβ antibodies have been demonstrated not to have much success. As a result, treatments that can successfully postpone or reverse the course of the disease are urgently needed. Investigation of the mechanisms of action (MoAs) that are known about amyloid allows for more effective drug target discovery and innovative therapy development. For this purpose, Creative Biolabs provides a wide range of in vivo, in vitro, and ex vivo assays that allow researchers to have an optimized understanding of amyloid MoAs and thus drive early-stage drug development targeting neurotoxic molecular Aβ.

Amyloid MoA in AD

Understanding the MoAs of Aβ in Alzheimer's disease plays an essential role in drug discovery. Amyloid precursor protein (APP) cleavage by γ-secretase generates two main toxic forms of amyloid, Aβ40 and Aβ42 peptides, subsequently released from neurons. The overproduction or not seasonable clearance of extracellular Aβ is the initiate the AD, as it causes accumulation of Aβ monomers to form soluble Aβ oligomers, fibrils, and eventually amyloid plaques. Aβ oligomers can induce toxicity in synapses by binding to Aβ receptors such as EphA4, PrP^c, EphB2, NMDAR, and LiLRB2. Besides, Aβ oligomers also defect mitochondria function by stimulating caspase-3 activation, reducing ATP production, and enhancing ROS levels, hence aggravating synaptic dysfunction. In addition, Aβ oligomers can activate microglia-induced Aβ degradation by binding to Aβ receptors such as TREM2, TLR4, and CD36 to release proinflammatory cytokines. The accumulation of Aβ could also be a reactive compensatory response to neuronal impairment. It is imperative to design compounds that can reduce the Aβ production, antagonize accumulations, and eliminate Aβ plaques through targeting Aβ monomers, Aβ oligomers, and their receptors.

Fig.1 A model for Aβ-induced neurotoxicity and glial response in AD. (Guo, 2020)

Creative Biolabs offers a wide range of amyloid targeting therapies study services, including Aβ oligomerization assay, toxic Aβ exposure assay, Aβ induced toxicity assay, Aβ aggregates determination assay, as well as APP processing assay and gamma secretase activity assay. These assays allow researchers to potentially explore the impact of amyloid in AD pathogenesis, thereby exploring novel amyloid targeting therapies for AD. If you want to study amyloid in AD for your preclinical drug development projects, please contact us. We are ready to assist you to design your programs.

Reference

1. Guo, T.; et al. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease. Molecular neurodegeneration. 2020, 15 (1): 1-37.