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Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors.

ABSTRACT: Alzheimer's disease (AD) is characterized by deposition of amyloid beta (A?) peptides into senile plaques in the brain. While most familial mutations are associated with early-onset AD, recent studies report the AD-protective nature of two genetic human A? variants, i.e. A2T and A2V, in the heterozygous state. The mixture of A2V A?1-6 (A?₆) hexapeptide and WT A?1-42 (??₄₂) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T A?₆ hexapeptide binding on the monomeric WT A?₄₂ landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of A?₄₂ with the A2V and A2T hexapeptides compared to WT A?₆. A notable reorganization of the A?₄₂ landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, A?₆-bound A?₄₂ monomer exhibits alternative structural features that are strongly dependent on the hexapeptide sequence. For example, a central helix is more frequently populated within the A2T-bound monomer, while A2V-bound A?₄₂ is often enhanced in overall disorder. Taken together, the present simulations offer novel molecular insights onto the effect of the N-terminal hexapeptide binding on the A?₄₂ monomer structure, which might help in explaining their reported amyloid inhibition properties.

SUBMITTER: Chakraborty S

PROVIDER: S-EPMC5577341 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors.

Chakraborty Srirupa S Das Payel P

Scientific reports 20170830 1

Alzheimer's disease (AD) is characterized by deposition of amyloid beta (Aβ) peptides into senile plaques in the brain. While most familial mutations are associated with early-onset AD, recent studies report the AD-protective nature of two genetic human Aβ variants, i.e. A2T and A2V, in the heterozygous state. The mixture of A2V Aβ1-6 (Aβ<sub>6</sub>) hexapeptide and WT Aβ1-42 (Αβ<sub>42</sub>) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects o ...[more]

PMID: 28855598

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Project description:BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by accumulation of extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles, leading to chronic activation of astrocytes and microglia and persistent neuroinflammation. Aβ-linked activation of microglia and astrocytes leads to increased intracellular calcium and production of proinflammatory cytokines, impacting the progression of neurodegeneration. An N-terminal Aβ fragment (Aβ1-15) and a shorter hexapeptide core sequence within the N-Aβ fragment (N-Aβcore: Aβ10-15) have previously been shown to protect against Aβ-induced mitochondrial dysfunction, oxidative stress and apoptosis in neurons and rescue synaptic and spatial memory deficits in an APP/PSEN1 mouse model. Here, we hypothesized that the N-Aβ fragment and N-Aβcore are protective against Aβ-induced gliotoxicity, promoting a neuroprotective environment and potentially alleviating the characteristically persistent neuroinflammation present in AD.MethodsWe treated ex vivo organotypic brain slice cultures from an aged familial AD mouse model, 5xFAD, with the N-Aβcore and used immunocytochemistry to assess the impact on astrogliosis and microgliosis and alterations in synaptophysin-positive puncta engulfed by microglia. Isolated neuron/glia cultures, mixed glial cultures or a microglial cell line were treated with oligomeric human Aβ at concentrations mimicking the pathogenic concentrations (μM) observed in AD in the absence or presence of the non-toxic N-terminal Aβ fragments. Resultant changes in synaptic density, gliosis, oxidative stress, mitochondrial dysfunction, apoptosis, and the expression and release of proinflammatory markers were then determined.ResultsWe demonstrate that the N-terminal Aβ fragments mitigated the phenotypic switch leading to astrogliosis and microgliosis induced by pathological concentrations of Aβ in mixed glial cultures and organotypic brain slice cultures from the transgenic 5xFAD mouse model, while protecting against Aβ-induced oxidative stress, mitochondrial dysfunction and apoptosis in isolated astrocytes and microglia. Moreover, the addition of the N-Aβcore attenuated the expression and release of proinflammatory mediators in microglial cells activated by Aβ and rescued microglia-mediated loss of synaptic elements induced by pathological levels of Aβ.ConclusionsTogether, these findings indicate the protective functions of the N-terminal Aβ fragments extend to reactive gliosis and gliotoxicity induced by Aβ, by preventing or reversing glial reactive states indicative of neuroinflammation and synaptic loss central to AD pathogenesis.

Dataset Information

Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors.

Publications

Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors.

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