Novel Anti-Alzheimer’s Therapeutic Molecules Targeting Amyloid Precursor Protein Processing

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia among older people, and the prevalence of this disease is estimated to rise quickly in the upcoming years. Unfortunately, almost all of the drug candidates tested for AD until now have failed to exhibit any efficacy. Henceforth, there is an increased necessity to avert and/or slow down the advancement of AD. It is known that one of the major pathological characteristics of AD is the presence of senile plaques (SPs) in the brain. These SPs are composed of aggregated amyloid beta (Aβ), derived from the amyloid precursor protein (APP). Pharmaceutical companies have conducted a number of studies in order to identify safe and effective anti-Aβ drugs to combat AD. It is known that α-, β-, and γ-secretases are the three proteases that are involved in APP processing. Furthermore, there is a growing interest in these proteases, as they have a contribution to the modulation and production of Aβ. It has been observed that small compounds can be used to target these important proteases. Indeed, these compounds must satisfy the common strict requirements of a drug candidate targeted for brain penetration and selectivity toward different proteases. In this article, we have focused on the auspicious molecules which are under development for targeting APP-processing enzymes. We have also presented several anti-AD molecules targeting Aβ accumulation and phosphorylation signaling in APP processing. This review highlights the structure-activity relationship and other physicochemical features of several pharmacological candidates in order to successfully develop new anti-AD drugs.

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“…Depending on the previous molecular insight, Ghosh and Tang were able to develop OM00-3 inhibitor (inhibitor 2) by further optimization of their octapeptide inhibitor structure (OM99-2) (Turner et al 2001). OM00-3 ( Fig.…”

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“…The amyloid precursor protein (APP) is a type I transmembrane glycoprotein containing 695–770 amino acids [ 50 ]. It is regarded that abnormal proteolytic processing of APP leads to the generation of Aβ [ 51 ].…”

“…In the amyloidogenic pathways, APP is cleaved by β- and γ-secretases [ 50 ]. β-secretase (BACE1) belongs to the aspartic protease family and is around 500 residues in length containing 2 active sites situated at the lumenal side of the membrane [ 52 ].…”

Emerging Promise of Cannabinoids for the Management of Pain and Associated Neuropathological Alterations in Alzheimer’s Disease

“…Some events such as increased generation, oligomerization as well as accumulation of Aβ are the key factors at the beginning stage of AD. The noxious Aβ peptides including Aβ 40 and Aβ 42 are formed by the amyloid precursor protein (APP) through the cleavage by β- and γ-secretases ( Kabir et al., 2020a ; Uddin et al., 2020e ; Uddin et al., 2020j ). Moreover, APP is one of the transmembrane proteins that is folded and altered in the endoplasmic reticulum (ER) as well as transferred via the Golgi complex to the external membrane.…”