IAPP Mimic Blocks Aβ Cytotoxic Self‐Assembly: Cross‐Suppression of Amyloid Toxicity of Aβ and IAPP Suggests a Molecular Link between Alzheimer's Disease and Type II Diabetes

Background: Inhibition of pathogenic protein aggregation by small molecules is poorly understood. Results: Aggregation inhibitors alter the free energy landscape of a relevant fragment of Alzheimer amyloid-␤ peptide in subtle but complex fashion. Conclusion: Intrinsic disorder of disease proteins persists at the level of binding small molecules. Significance: Hallmark characteristics and efficacy of inhibitors can be reconciled with lack of specificity.

mentioning

confidence: 99%

Disordered Binding of Small Molecules to Aβ(12–28)

Convertino

Vitalis

Caflisch

2011

“…Inhibition of oligomer formation is one possible therapeutic strategy to improve cognition (2,3). Oligomer and fibril formation are sensitive to the environment.…”

mentioning

confidence: 99%

Polymorphic Triple β-Sheet Structures Contribute to Amide Hydrogen/Deuterium (H/D) Exchange Protection in the Alzheimer Amyloid β42 Peptide

Nussinov

2011

Background: Experimental structural elucidation of polymorphic amyloid ensembles is difficult. Results: We found a novel amyloid structural motif of a triple ␤-sheet by comparing computational and experimental H/D exchange. Conclusion:The triple ␤-sheet A␤42 has a minimal exposure of hydrophobic residues and is further stabilized by the E22Q (Dutch) mutation in Alzheimer disease. Significance: The finding helps to understand the Dutch mutation in Alzheimer disease.

“…However, IAPP binds to prefibrillar A␤40 and blocks the cytotoxicity of A␤ aggregates. 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).…”

Section: Iappmentioning

confidence: 99%

“…In contrast, ␣-syn (23), tau (28), and fibrinogen-␣ (95) promote A␤ toxicity and/or fibrillation and increase the risk of AD in mice (32) and/or patients (25,76). IAPP prevents A␤ fibrillation in vitro (50), yet IAPP-associated T2D may promote AD progression in vivo. The different ways amyloid proteins modulate A␤ fibrillation may depend on their varying structures and stabilities.…”

Section: Implications Of A␤ Cross-amyloid Interactionsmentioning

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

125

108

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...