Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease

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.

Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

“…Other mutations such as T714I, V715A, V715M, V717I, V717L, L723P, K724N, and I716V affect the γ-secretase cleavage site and cause an increase in the Aβ42/Aβ40 ratio, while E693G, E693K, D694N, and A692G mutations affect the α-secretase cleavage site and cause polymorphic aggregates with the ability to disrupt bilayer integrity. Also, the E693delta is a deletion mutation that enhances the formation of synaptotoxic Aβ [ 51 , 52 ].…”

Highlighting membrane protein structure and function: A celebration of the Protein Data Bank

“…Validated by mouse gene knockouts, BACE1 and related γsecretase (66-68) are thus targets for drugs (69,70). In spite of extremely difficult clinical trials, these targets remain as promising modulators of Alzheimer's disease (71). Many of the intramembrane proteases destabilize the α-helical regions that characterize transmembrane proteins and often don't rely on specific amino acid side chains for specificity as do the soluble proteases.…”

Role of Exosomes in Brain Diseases

“…The disparate modification of Amyloid beta (Aβ) peptide and tau protein in the damaged brain regions are considered characteristic features of Alzheimer's disease (AD). The former is degraded by APP (Luciunaite et al, 2020 ; Zhao et al, 2020 ). Over phosphorylation of tau proteins can lead to dissociation of tau proteins from microtubules and aggregation with each other, forming neurofibrillary tangles and deposition in neuronal cell bodies as well as axons and dendrites (Vandendriessche et al, 2020 ).…”