Disease Modifying Therapies for Alzheimer's Disease Targeting A<b><i>β</i></b>Oligomers: Implications for Therapeutic Mechanisms

Matsubara, Etsuro; Takamura, Ayumi; Okamoto, Yoshiwo; Oono, Hideto; Nakata, Takashi; Wakasaya, Yasuhito; Kawarabayashi, Tatsuhiko; Shoji, Mikio

doi:10.1155/2013/984041

Cited by 8 publications

(4 citation statements)

References 36 publications

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“…These antibodies reduce tau pathology, also seen earlier with the broader-based A11 oligomer antibody [132]. Another AβO antibody (72D9) sequestered both extracellular and intraneuronal AβOs [115]. Sequestering AβOs in older Tg mice attenuates synapse loss near plaques and abolishes loss further away [31].…”

Section: Therapeuticsmentioning

confidence: 96%

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

2015

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Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson’s and Alzheimer’s. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer’s dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca2+ overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer’s disease.

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Section: Therapeuticsmentioning

confidence: 96%

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

2015

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“…Another important factor in the present study was that anti-AβO Fabs could reduce various toxic Aβ species, including AβOs, toxic Aβ conformers, and N3pE Aβs. We previously demonstrated that anti-AβO antibodies lead AβOs to form nonfibrillar amorphous structures and play an important chaperone-like role in the Aβ aggregation pathway and allow Aβ to exist in a non-toxic state using a ThT assay and electron microscopy [ 21 ]. The present study verified the inhibitory effect on Aβ42 aggregation using a ThT assay and found that only 6H4 showed a long-lasting inhibitory effect on Aβ aggregation, such as primary nucleation and seeds (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The impact of 6H4 on Aβ42 aggregation was evaluated using a ThT assay as described previously [ 13 , 21 ]. Briefly, Aβ42 (Merck, AG968) was monomerized with hexasuppleisopropanol and dissolved in 1% NH 4 OH.…”

Section: Methodsmentioning

confidence: 99%

Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain

et al. 2023

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Background Although a large amount of evidence has revealed that amyloid β (Aβ), especially Aβ oligomers, protofibrils, and pyroglutamated Aβs, participate primarily in the pathophysiological processes of Alzheimer’s disease, most clinical trials of anti-Aβ antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood–brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aβ oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer’s disease pathology in Alzheimer’s disease model mice at the age of emergence of early Alzheimer’s disease pathology. Results During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aβ species, such as Aβ oligomers, toxic Aβ conformers, and pyroglutamated Aβs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aβ plaques, Aβ-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimer’s disease. Conclusions The results indicated that the strategy of reducing toxic Aβ species in early dementia owing to Alzheimer’s disease by providing sufficient antibodies in the brain may modify Alzheimer’s disease progression.

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“…Although a wide variety of organic compounds have been shown to inhibit Aβ 1–42 aggregation ( Fig 6 ) [ 10 – 15 ], many of them cannot be used because they are cytotoxic in cultured cells, favor the formation of oligomeric species, or have low bioavailability due to high molecular weights (>500 g/mol), which makes it difficult for them to cross lipid layers [ 42 ]. Because the cytotoxicity and genotoxicity of curcumin has been demonstrated in some cultured cells [ 47 ], several chemical analogs have been designed to overcome these limitations [ 12 ]. In addition, the activity of 1,2,3-hydroxyl- scyllo- inositol ( Fig 6 ) as a fibril-forming inhibitor has been demonstrated by ThT fluorescence and AFM [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Virtual and In Vitro Screens Reveal a Potential Pharmacophore that Avoids the Fibrillization of Aβ1–42

et al. 2015

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Among the multiple factors that induce Alzheimer’s disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1–42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1–42 pathological aggregation represents a field of research interest. Several Aβ1–42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1–42 in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1–42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1–42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species.

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Disease Modifying Therapies for Alzheimer's Disease Targeting AβOligomers: Implications for Therapeutic Mechanisms

Cited by 8 publications

References 36 publications

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain

Virtual and In Vitro Screens Reveal a Potential Pharmacophore that Avoids the Fibrillization of Aβ1–42

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