Dysregulated Metabolism of the Amyloid-β Protein and Therapeutic Approaches in Alzheimer Disease.
Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives. While the etiology of AD remains an enigma, excessive accumulation of β-amyloid peptide (Aβ) is widely believed to induce pathological changes and cause dementia in brains of AD patients. BACE1 was discovered to initiate the cleavage of amyloid precursor protein (APP) at the β-secretase site. Only after this cleavage does γ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ. Hence, blocking BACE1 proteolytic activity will suppress Aβ generation. Due to the linkage of Aβ to the potential cause of AD, extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD therapy. With the recent breakthrough in developing brain-penetrable BACE1 inhibitors, targeting amyloid deposition-mediated pathology for AD therapy has now become more practical. This review will summarize various strategies that have successfully led to the discovery of BACE1 drugs, such as MK8931, AZD-3293, JNJ-54861911, E2609 and CNP520. These drugs are currently in clinical trials and their updated states will be discussed. With the promise of reducing Aβ generation and deposition with no alarming safety concerns, the amyloid cascade hypothesis in AD therapy may finally become validated.