Selectively N‐Methylated Soluble IAPP Mimics as Potent IAPP Receptor Agonists and Nanomolar Inhibitors of Cytotoxic Self‐Assembly of Both IAPP and Aβ40

Yan, Limei; Velkova, Aleksandra; Tatarek‐Nossol, Marianna; Rammes, Gerhard; Sibaev, Andrei; Andreetto, Erika; Kracklauer, Michael; Bakou, Maria; Malideli, Eleni; Göke, Burkhard; Schirra, Jörg; Storr, Martin; Kapurniotu, Aphrodite

doi:10.1002/anie.201302840

Cited by 45 publications

(88 citation statements)

References 38 publications

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“…Additionally, amylin likely improves glucose metabolism in the brain since it readily crosses the BBB [21], relaxes cerebrovascular structures thereby increasing blood supply to the brain [4, 5], and is shown to enhance neural regeneration [6]. Several studies have shown that monomeric amylin and its analogs inhibit the formation of Aβ aggregation, a key element in the AD pathogenesis [22–26]. These results taken together could account for its positive association with cognition in elderly adults in this study.…”

Section: Discussionmentioning

confidence: 99%

Positive Association between Plasma Amylin and Cognition in a Homebound Elderly Population

Qiu

Zhu

et al. 2014

JAD

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Our recent study reported that amylin, a pancreatic peptide that readily crosses the blood-brain barrier, improves learning and memory in Alzheimer’s disease mouse models. However, the relationship between peripheral amylin and cognition in humans is unknown. In this follow-up study, using a cross-sectional, homebound elderly population, improvement in cognitive function with increasing quartiles of plasma amylin was suggested by positive association with verbal memory (p = 0.0002) and visuoconstruction tasks (p = 0.004), and inverse association with timed measures of attention (p < 0.0001) and executive function (p = 0.04). After adjusting for demographic information, apolipoprotein E4 allele, diabetes, stroke, kidney function, and lipid profile, log10 of plasma amylin remained associated with these cognitive domains. In contrast, plasma amyloid-β peptide was not associated with these specific cognitive domains. Our study suggests that peripheral amylin may be protective for cognitive decline, especially in the domains affected by Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

Positive Association between Plasma Amylin and Cognition in a Homebound Elderly Population

Qiu

Zhu

et al. 2014

JAD

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“…N-methyl peptides N-methylation of an SRE has one side able to bind to the target by hydrogen bonding (H-bond), while the other has an N-methyl in place of backbone H, thus preventing Hbonds. Selectively N-methylated soluble IAPP (islet amyloid polypeptide peptide) mimics nanomolar inhibitors of cytotoxic self-assembly of both IAPP and Ab1-40 [10].…”

Section: Retro-inverso (Ri) Peptidesmentioning

confidence: 99%

Inhibition of protein aggregation and amyloid formation by small molecules

Doig

Derreumaux

2015

Current Opinion in Structural Biology

276

209

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“…Conversely, A␤ binds prefibrillar IAPP, and A␤ and IAPP aggregates reciprocally regulate each other's cytotoxicity (50). IAPP inhibits the cytotoxicity of A␤ aggregates at nanomolar concentrations and inhibits A␤ fibrillation at stoichiometric ratios (51). Several small A␤ fragments bind to full-length IAPP, some with nanomolar affinity (52).…”

Section: Iappmentioning

confidence: 99%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

128

108

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Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-␤ (A␤) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A␤ and other amyloid proteins.Alzheimer disease (AD) 3 is the most common form of elderly dementia. Its causes have not yet been clearly elucidated. The two classical AD lesions are depositions of intracellular neurofibrillary tau tangles and extracellular deposits of aggregated amyloid-␤ (A␤) peptides in amyloid plaques in the gray matter of the brain, mainly the hippocampus and neocortex. A␤ is a 36 -43-residue peptide cleaved from the amyloid-␤ protein precursor (A␤PP) by ␥-secretase and ␤-secretase enzymes.Some A␤PP and A␤ mutations increase A␤ production and deposition and/or extend the half-life of A␤ in the brain, but only a fraction (5%) of Alzheimer disease is familial AD (1). Several studies indicate that alterations of the pathologies of other amyloid proteins such as ␣-synuclein (2) and tau (3) are observed in familial AD.The amyloid cascade hypothesis suggests that deposition of A␤ aggregates in brain plays a vital role in AD development (4). The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not. Missense mutations in the A␤PP, apoE, PS1, and PS2 genes can increase accumulation and toxicity of A␤ aggregates, and the "on-pathway" intermediate aggregates seem to be the most cell-damaging species (6). This provides strong support for the amyloid cascade hypothesis, which nevertheless remains disputed.Although two recent reviews (7, 8) respectively reject and support the amyloid cascade hypothesis, they both agree on one poin...

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Selectively N‐Methylated Soluble IAPP Mimics as Potent IAPP Receptor Agonists and Nanomolar Inhibitors of Cytotoxic Self‐Assembly of Both IAPP and Aβ40

Cited by 45 publications

References 38 publications

Positive Association between Plasma Amylin and Cognition in a Homebound Elderly Population

Positive Association between Plasma Amylin and Cognition in a Homebound Elderly Population

Inhibition of protein aggregation and amyloid formation by small molecules

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

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