Aβ_8-20 Fragment as an Anti-Fibrillogenic and Neuroprotective Agent: Advancing toward Efficient Alzheimer’s Disease Treatment

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by a spectrum of symptoms associated with memory loss and cognitive decline with deleterious consequences in everyday life. The lack of specific drugs for the treatment and/or prevention of this pathology makes AD an ever-increasing economic and social emergency. Oligomeric species of amyloid-beta (Aβ) are recognized as the primary cause responsible for synaptic dysfunction and neuronal degeneration, playing a crucial role in the onset of the pathology. Several studies have been focusing on the use of small molecules and peptides targeting oligomeric species to prevent Aβ aggregation and toxicity. Among them, peptide fragments derived from the primary sequence of Aβ have also been used to exploit any eventual recognition abilities toward the full-length Aβ parent peptide. Here, we test the Aβ8‑20 fragment which contains the self-recognizing Lys-Leu-Val-Phe-Phe sequence and lacks Arg 5 and Asp 7 and the main part of the C-terminus, key points involved in the aggregation pathway and stabilization of the fibrillary structure of Aβ. In particular, by combining chemical and biological techniques, we show that Aβ8‑20 does not undergo random coil to β sheet conformational transition, does not form amyloid fibrils by itself, and is not toxic for neuronal cells. Moreover, we demonstrate that Aβ8‑20 mainly interacts with the 4–11 region of Aβ1‑42 and inhibits the formation of toxic oligomeric species and Aβ fibrils. Finally, our data show that Aβ8‑20 protects neuron-like cells from Aβ1‑42 oligomer toxicity. We propose Aβ8‑20 as a promising drug candidate for the treatment of AD.

Characterizing the Oligomers Distribution along the Aggregation Pathway of Amyloid Aβ1‐40 by NMR

“…We hypothesized that this unexpected behavior could be ascribed to small amount of Aβ1‐40 fragments present in the sample and generated by peptide degradation. This hypothesis agrees with literature data demonstrating that several Aβ fragments are effectively able to inhibit fibril formation for both Aβ1‐40 and Aβ1‐42 [53–55] . Considering these results, only highly pure samples (>95 %) were used in our analysis.…”

“…This hypothesis agrees with literature data demonstrating that several Aβ fragments are effectively able to inhibit fibril formation for both Aβ1-40 and Aβ1-42. [53][54][55] Considering these results, only highly pure samples (> 95 %) were used in our analysis. However, additional studies will be undertaken to further explore this issue.…”

Mechanism Explanation on Improved Cognitive Ability of D-Gal Inducing Aged Mice Model by Lactiplantibacillus plantarum MWFLp-182 via the Microbiota–Gut–Brain Axis

“…2 Despite numerous studies and clinical trials focused on AD, no currently available drugs are capable of alleviating its symptoms. 3 Therefore, it is crucial to implement preventive measures to reduce the incidence of AD by addressing neuroinflammation and oxidative stress during the aging process. 4 Recent studies have reported that dysregulation of the gut microbiota is directly or indirectly linked to cognitive function, and the gut−brain axis could improve cognitive injury by regulating gut microbiota.…”

“…Accumulated evidence suggests that oxidative stress and neuroinflammation can activate microglia, an early symptom in the development of Alzheimer’s disease (AD) . Despite numerous studies and clinical trials focused on AD, no currently available drugs are capable of alleviating its symptoms . Therefore, it is crucial to implement preventive measures to reduce the incidence of AD by addressing neuroinflammation and oxidative stress during the aging process …”

A Photolabile Curcumin‐Diazirine Analogue Enables Phototherapy with Physically and Molecularly Produced Light for Alzheimer's Disease Treatment**

“…[7] Current preclinical and clinical AD drugs primarily aim to the reduction of Aβ production, prevention of Aβ aggregation, and promotion of Aβ clearance. [8] Recent studies have explored strategies to reduce Aβ neurotoxicity by altering the amino acid structures within the Aβ sequence, [9] particularly through catalytic photooxygenation of Aβ approaches. [10] However, these earlier studies have predominantly depended on the use of external physical light sources, resulting in limited light penetration of brains and posing a challenge for future clinical applications.…”