Abstract
Alzheimer’s disease (AD) is the most common type of senile dementia, characterized by neurofibrillary tangle and amyloid plaque in brain pathology. Major efforts in AD drug were devoted to the interference with the production and accumulation of amyloid-β peptide (Aβ), which plays a causal role in the pathogenesis of AD. Aβ is generated from amyloid precursor protein (APP), by consecutive cleavage by β-secretase and γ-secretase. Therefore, β-secretase and γ-secretase inhibition have been the focus for AD drug discovery efforts for amyloid reduction. Here, we review β-secretase inhibitors and γ-secretase inhibitors/modulators, and their efficacies in clinical trials. In addition, we discussed the novel concept of specifically targeting the γ-secretase substrate APP. Targeting amyloidogenic processing of APP is still a fundamentally sound strategy to develop disease-modifying AD therapies and recent advance in γ-secretase/APP complex structure provides new opportunities in designing selective inhibitors/modulators for AD.
Highlights
Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, characterized by progressive and irreversible loss of memory
older living with AD's dementia in the United States is projected to grow from
Cognitive deficits caused by AD
Summary
Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, characterized by progressive and irreversible loss of memory. AD is the leading cause of senile dementia. The number of people age 65 and older living with AD’s dementia in the United States is projected to grow from 5.8 million in 2020 to 13.8 million by 2050 (Alzheimer’s_Association, 2020). Cognitive deficits caused by AD, such as progressive memory loss, difficulty in communication and movement disorder, significantly compromise the patients’ quality of life, leading to hospitalization and eventually death due to complications. Total medical expenses for Alzheimer’s or other dementias in the United States are projected to be $305 billion in 2020 (Alzheimer’s_Association, 2020). There is a major unmet medical need for disease-modifying therapies for AD
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