A mimotope of Aβ oligomers may also behave as a β‐sheet inhibitor

Abstract

Beta-amyloid (Aβ) oligomers are strongly associated with the cascade of harmful events leading to neurodegeneration in Alzheimer's disease (AD). Elimination of Aβ oligomers or inhibition of Aβ assembly is a valuable therapeutic approach for the treatment of AD. Here, we obtained a mimotope of Aβ oligomers, AOEP2, by screening a peptide library using oligomer-specific antibodies. The antibodies induced by AOEP2 specifically recognize Aβ oligomers rather than monomers and fibrils. Interestingly, the AOEP2 peptide binds to Aβ monomers and inhibits the formation of Aβ oligomers and β-sheet structure, reduces Aβ42-induced neurotoxicity, and decreases the release of proinflammatory cytokines. Taken together, AOEP2, a novel multifunctional peptide directly or indirectly targeting Aβ, has promising therapeutic potential for AD.

Peptides, Peptidomimetics, and Carbohydrate–Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer’s Disease

“…Liu and co-workers identified a mimotope of the Aβ oligomer from a phase-display library using oligomer specific antibodies . AOEP2 (FDYKAEFMPWDT) bound Aβ 42 concentration-dependently during ELISA studies and, once spotted onto nitrocellulose membrane, exhibited binding to all three of monomeric, oligomeric and fibrillar Aβ.…”

“…AOEP2 also lowered Aβ 42 β-sheet content and attenuated Aβ 42 -induced cytotoxicity concentration-dependently. Additionally, AOEP2 significantly decreased production of proinflammatory cytokines TNF-α and IL-6 dose-dependently …”

“…Additionally, AOEP2 significantly decreased production of proinflammatory cytokines TNF-α and IL-6 dose-dependently. 128 Carnosine, a naturally occurring imidazole dipeptide, has exhibited inhibitory properties against toxicity and aggregation of multiple amyloidogenic species including Aβ, natural 143 and glycated α-Crystallin, 144 hen egg-white lysozyme (HEWL), 145 and prion protein. 146 It has exhibited protection of rat brain endothelial cells and rat PC12 cells against toxicity mediated by Aβ peptides 147,148 and, when orally administered, reduced interneuronal Aβ accumulation, improved AD-related mitochondrial dysfunction and recovered the activity of hippocampal and cerebral complexes within AD-transgenic mice.…”

Modulation of aggregation with an electric field; scientific roadmap for a potential non-invasive therapy against tauopathies

“…1 Although this number is expected to increase to 132 million by 2050, there is no clinically approved therapy to cure or retard its progression. 1 Promising therapeutic strategies under research include native state stabilisation or brillation inhibition using small molecules, 2-6 immunotherapy, 7,8 peptide or peptidomimetics, [9][10][11][12][13][14][15][16][17][18] nanoparticles, 19,20 transient metals, [21][22][23][24] supramolecular inhibition of brillation 25,26 and sequestering the monomeric form of the peptide. 27 Nucleation-dependent aggregation is one of the most accepted models for the formation of amyloid brils.…”

Promising Results from Alzheimer’s Disease Passive Immunotherapy Support the Development of a Preventive Vaccine

“…Nonetheless, that the protective antibodies induced by this mimotope target the A β Os rather than the monomeric forms strengthens the idea that soluble A β aggregates are one of the critical etiological agents in AD. The fact that the dodecapeptide forming the mimotope, when used by itself, can bind to A β monomers and inhibit the formation of cytotoxic A β Os [36], highlights its therapeutic potential to prevent the damaging A β aggregation leading to neurotoxicity.…”