Amyloid ß-Targeted Inhibitory Peptides for Alzheimer’s Disease: Current State and Future Perspectives

Jokar, Safura; Khazaei, Saeedeh; Gameshgoli, Xaniar Esmailzadeh; Khafaji, Mona; Yarani, Behnam; Sharifzadeh, Mohammad; Beiki, Davood; Bavi, Omid

doi:10.36255/exonpublications.alzheimersdisease.2020.ch3

Cited by 9 publications

(7 citation statements)

References 107 publications

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“…-are too weak to go all the down the bench-to-bedside route [36,37], (ii) the timing of therapeutic intervention-which should be very early along the natural history of the disease-(iii) the phenotypic variability of AD [38]-that deeply affects and diversifies the responsiveness to treatments-and (iv) the complexity of disease pathogenesis suggesting that more than one target should be locked by therapeutic strategies to be successful in tackling the illness [7,39,40]. Overall these observations suggest that the optimal therapeutic strategy against AD should engage multiple allied molecular mechanisms, demonstrating efficacy not only in interfering with the well-known players in AD pathogenesis-i.e., Aβ, tau, neuroinflammation and others-but also in hindering their neurotoxic effects.…”

Section: Discussionmentioning

confidence: 99%

“…The approach based on D-peptides is very promising because of their characteristics including high resistance to protease digestion, stability, and bioavailability [37], which make them optimal molecular prototypes for the development of drugs for the treatment of neurological disorders [55]. Actually, Aβ1-6 A2V (D) may be included in the class of 'amyloid β-targeted peptide inhibitors', which have special properties, including high selectivity, low accumulation in tissues, low side-effects and toxicity, and different chemical and biological synthesis routes when compared with other compounds used for therapeutic purposes [36,56,57].…”

Section: Discussionmentioning

confidence: 99%

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A novel bio-inspired strategy to prevent amyloidogenesis and synaptic damage in Alzheimer’s disease

et al. 2022

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Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder that affects millions of people worldwide. AD pathogenesis is intricate. It primarily involves two main molecular players—amyloid-β (Aβ) and tau—which actually have an intrinsic trend to generate molecular assemblies that are toxic to neurons. Incomplete knowledge of the molecular mechanisms inducing the onset and sustaining the progression of the disease, as well as the lack of valid models to fully recapitulate the pathogenesis of human disease, have until now hampered the development of a successful therapy for AD. The overall experience with clinical trials with a number of potential drugs—including the recent outcomes of studies with monoclonal antibodies against Aβ—seems to indicate that Aβ-targeting is not effective if it is not accompanied by an efficient challenge of Aβ neurotoxic properties. We took advantage from the discovery of a naturally-occurring variant of Aβ (AβA2V) that has anti-amyloidogenic properties, and designed a novel bio-inspired strategy for AD based on the intranasal delivery of a six-mer peptide (Aβ1-6A2V) retaining the anti-amyloidogenic abilities of the full-length AβA2V variant. This approach turned out to be effective in preventing the aggregation of wild type Aβ and averting the synaptic damage associated with amyloidogenesis in a mouse model of AD. The results of our preclinical studies inspired by a protective model already existing in nature, that is the human heterozygous AβA2V carriers which seem to be protected from AD, open the way to an unprecedented and promising approach for the prevention of the disease in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A novel bio-inspired strategy to prevent amyloidogenesis and synaptic damage in Alzheimer’s disease

et al. 2022

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“…Safura Jokar et al. have demonstrated that the KLVFFA peptide segment which is considered as the short active sequence of the β‐Amyloid peptide related to Alzheimer's disease (AD), [28–31] could self‐assemble, as the residues have a central hydrophobic core (CHC), that can act as the critical nucleation site [32] …”

Section: Introductionmentioning

confidence: 99%

“…[27] Safura Jokar et al have demonstrated that the KLVFFA peptide segment which is considered as the short active sequence of the β-Amyloid peptide related to Alzheimer's disease (AD), [28][29][30][31] could self-assemble, as the residues have a central hydrophobic core (CHC), that can act as the critical nucleation site. [32] The above-mentioned aggregation in the majority are reported mostly in organic solvent, where water is used as cosolvent in a few cases. However, it would not be determined whether the driving factor is the aromatic moiety (Fmoc) associated at the N-terminal, or the conjugate effect of both the N-terminal protecting group along with the aromatic residue in the hydrophobic solvent.…”

Section: Introductionmentioning

confidence: 99%

FF Activates Nucleation for Aggregation in Aqueous Medium: A Key Insight of Amyloid Plaque Formation

Roy,

Ghosh,

Mukherjee

et al. 2024

ChemistrySelect

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Molecular self‐association of monomers with multifaceted cross‐linkers, opens new possibilities for the development of various supramolecular‐networks that enable to participate in different functions. Plaques associated with senility that form in the brains of Alzheimer′s patients are mainly composed of beta amyloid (Aβ). It can be assumed that there must be a nucleation site which through reverse folding initiate to aggregate this Aβ plaque. It has been reported KLVFFA motif of Aβ sequence plays an important role as the amylogenic unit for Alzheimer disease. In order to identify the shortest sequence that would initiate the nucleation for such aggregation, we have synthesized N‐terminal protected two two‐residue peptides [Hex‐Phe(1)‐Phe(2)‐OMe: (FF)] and [Hex‐Phe(1)‐Ala(2)‐OMe: (FA)] an important fragment of KLVFFA motif. Using various microscopic and biophysical approaches, including measuring the hydrodynamic radii, it is observed that in fully aqueous condition in comparison to FA, FF nucleates higher degree of aggregates, along with substantial formation of dendrimeric amyloid fibrils, which has been elegantly visualized in Congo‐red assay through formation of distinct apple‐green birefringence. Such an observation leads to hypothesize that the ‘di‐phenylalanine’ unit (FF) plays a crucial role as the nucleation site towards attaining the aggregate for formation of the Aβ plaque through reverse folding.

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“…Ab42 contains two hydrophobic regions, Ala30-Val36 (at the C terminal) and Leu17-Ala21, referred to as the Central Hydrophobic Core (CHC) [28,29]. Ab-based peptide inhibitors are based on the structure of the C-terminal fragments (CTF) and the CHC sequences of the Ab peptide [30]. They bind to the Ab peptide at specific sites and prevent its assembly into amyloid fibrils.…”

Section: Introductionmentioning

confidence: 99%

A Copper-Selective Sensor and Its Inhibition of Copper-Amyloid Beta Aggregation

Nguyen,

Poduska,

Franks

et al. 2024

Biosensors

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Copper is an essential trace metal for biological processes in humans and animals. A low level of copper detection at physiological pH using fluorescent probes is very important for in vitro applications, such as the detection of copper in water or urine, and in vivo applications, such as tracking the dynamic copper concentrations inside cells. Copper homeostasis is disrupted in neurological diseases like Alzheimer’s disease, and copper forms aggregates with amyloid beta (Ab42) peptide, resulting in senile plaques in Alzheimer’s brains. Therefore, a selective copper detector probe that can detect amyloid beta peptide-copper aggregates and decrease the aggregate size has potential uses in medicine. We have developed a series of Cu2+-selective low fluorescent to high fluorescent tri and tetradentate dentate ligands and conjugated them with a peptide ligand to amyloid-beta binding peptide to increase the solubility of the compounds and make the resultant compounds bind to Cu2+–amyloid aggregates. The copper selective compounds were developed using chemical scaffolds known to have high affinity and selectivity for Cu2+, and their conjugates with peptides were tested for affinity and selectivity towards Cu2+. The test results were used to inform further improvement of the next compound. The final Cu2+ chelator–peptide conjugate we developed showed high selectivity for Cu2+ and high fluorescence properties. The compound bound 1:1 to Cu2+ ion, as determined from its Job’s plot. Fluorescence of the ligand could be detected at nanomolar concentrations. The effect of this ligand on controlling Cu2+–Ab42 aggregation was studied using fluorescence assays and microscopy. It was found that the Cu2+–chelator–peptide conjugate efficiently reduced aggregate size and, therefore, acted as an inhibitor of Ab42-Cu2+ aggregation. Since high micromolar concentrations of Cu2+ are present in senile plaques, and Cu2+ accelerates the formation of toxic soluble aggregates of Ab42, which are precursors of insoluble plaques, the developed hybrid molecule can potentially serve as a therapeutic for Alzheimer’s disease.

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Amyloid ß-Targeted Inhibitory Peptides for Alzheimer’s Disease: Current State and Future Perspectives

Cited by 9 publications

References 107 publications

A novel bio-inspired strategy to prevent amyloidogenesis and synaptic damage in Alzheimer’s disease

A novel bio-inspired strategy to prevent amyloidogenesis and synaptic damage in Alzheimer’s disease

FF Activates Nucleation for Aggregation in Aqueous Medium: A Key Insight of Amyloid Plaque Formation

A Copper-Selective Sensor and Its Inhibition of Copper-Amyloid Beta Aggregation

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