A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APPSwe/PSEN1ΔE9 Mice Model of Amyloid Pathology

Abstract

The progress in Alzheimer’s disease (AD) treatment suggests a combined therapeutic approach targeting the two lesional processes of AD, which include amyloid plaques made of toxic Aβ species and neurofibrillary tangles formed of aggregates of abnormally modified Tau proteins. A pharmacophoric design, novel drug synthesis, and structure-activity relationship enabled the selection of a polyamino biaryl PEL24-199 compound. The pharmacologic activity consists of a non-competitive β-secretase (BACE1) modulatory activity in cells. Curative treatment of the Thy-Tau22 model of Tau pathology restores short-term spatial memory, decreases neurofibrillary degeneration, and alleviates astrogliosis and neuroinflammatory reactions. Modulatory effects of PEL24-199 towards APP catalytic byproducts are described in vitro, but whether PEL24-199 can alleviate the Aβ plaque load and associated inflammatory counterparts in vivo remains to be elucidated. We investigated short- and long-term spatial memory, Aβ plaque load, and inflammatory processes in APPSwe/PSEN1ΔE9 PEL24-199 treated transgenic model of amyloid pathology to achieve this objective. PEL24-199 curative treatment induced the recovery of spatial memory and decreased the amyloid plaque load in association with decreased astrogliosis and neuroinflammation. The present results underline the synthesis and selection of a promising polyaminobiaryl-based drug that modulates both Tau and, in this case, APP pathology in vivo via a neuroinflammatory-dependent process.

Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review

“…Tautou et al, conducted clinical trials of the polyamine compound PEL24-199 using APP/PS1 transgenic mice, a model of Alzheimer’s disease. Increased concentrations of β-amyloid can cause damage associated with oxidative stress and inflammation and can up-regulate the levels and phosphorylation of the Tau protein, which consequently results in, for example, the formation of neurofibrillary tangles and the malfunctioning of neural synapses or neuronal death [ 78 ]. The authors hypothesized that a therapeutic approach that targeted amyloid deposits could be an effective way to halt the progression of the disease and, in the future, may even lay the groundwork for a complete cure for Alzheimer’s patients.…”

“…The tested compound, which had β-amyloid as its target, effectively abolished the process of neuro degradation caused by neuroinflammatory mechanisms. This shows that the process of accumulation of β-amyloid deposits is one of the many important causes of the development of neuroinflammation [ 78 ].…”

Sensorineural hearing loss and cognitive impairment: three hypotheses

“…Amyloid plaques formed by β-amyloid (Aβ) and neurofibrillary tangles formed by abnormally modified tau proteins are the hallmarks of AD ( Skouras et al, 2020 ; Ossenkoppele et al, 2022 ; Tautou et al, 2023 ). Aβ is a peptide produced by hydrolysis of amyloid precursor protein (APP), and excess Aβ accumulation in mitochondria activates astrocytes and microglia, damages neurons ( Huang et al, 2023 ), and induces mitochondrial autophagy, promoting reactive oxygen species (ROS) production and accelerating neural oxidation ( Dou and Tan, 2023 ).…”

β-Secretase-1: In Silico Drug Reposition for Alzheimer’s Disease

“…β-Amyloid is the product of the catabolism of a large protein, the β-Amyloid Precursor Protein (APP) [27][28][29]. Two proteases, β and γ secretase, endoproteolize the amyloid precursor protein (APP) to release the β-amyloid peptide [30][31][32]. In the brain of an Alzheimer's patient, abnormal levels of APP accumulate, forming plaques that coalesce between neurons, disrupting cell function and promoting neuronal death [8,32].…”

“…Two proteases, β and γ secretase, endoproteolize the amyloid precursor protein (APP) to release the β-amyloid peptide [30][31][32]. In the brain of an Alzheimer's patient, abnormal levels of APP accumulate, forming plaques that coalesce between neurons, disrupting cell function and promoting neuronal death [8,32]. β-secretase-1 (BACE-1) is a type of membrane-bound aspartic protease, which is 501 amino acids in length (five key domains, a signal peptide, and pro-catalytic, catalytic, transmembrane, and cytoplasmic domains have been identified in the enzyme) [23].…”