Abstract
The amyloid-β42 (Aβ42) peptide is believed to be the main culprit in the pathogenesis of Alzheimer disease (AD), impairing synaptic function and initiating neuronal degeneration. Soluble Aβ42 oligomers are highly toxic and contribute to progressive neuronal dysfunction, loss of synaptic spine density, and affect long-term potentiation (LTP). We have characterized a short, L-amino acid Aβ-oligomer Interacting Peptide (AIP) that targets a relatively well-defined population of low-n Aβ42 oligomers, rather than simply inhibiting the aggregation of Aβ monomers into oligomers. Our data show that AIP diminishes the loss of Aβ42-induced synaptic spine density and rescues LTP in organotypic hippocampal slice cultures. Notably, the AIP enantiomer (comprised of D-amino acids) attenuated the rough-eye phenotype in a transgenic Aβ42 fly model and significantly improved the function of photoreceptors of these flies in electroretinography tests. Overall, our results indicate that specifically “trapping” low-n oligomers provides a novel strategy for toxic Aβ42-oligomer recognition and removal.
Highlights
The amyloid-β 42 (Aβ 42) peptide is considered as the main culprit in the pathogenesis of Alzheimer disease (AD)[1], postulated to impair synaptic function and initiate neuronal degeneration[2,3]
To investigate the dynamics of Aβ 42 aggregation, the effect of Aβ -oligomer Interacting Peptide (AIP) on fibril formation was first examined by transmission electron microscopy (TEM)
As long-term potentiation (LTP) can be accompanied by structural modifications of dendritic spines, we examined the effect of AIP on theta-burst stimulation (TBS)-induced LTP in the presence of Aβ 42 in the CA1 region of mouse hippocampal slices
Summary
The amyloid-β 42 (Aβ 42) peptide is considered as the main culprit in the pathogenesis of Alzheimer disease (AD)[1], postulated to impair synaptic function and initiate neuronal degeneration[2,3]. Secreted Aβ 42 oligomers can disrupt cellular models of learning and memory, hippocampal long-term potentiation (LTP) in acute slices and in vivo, and impair the memory of a complex learned behavior in rats[15]. Such studies have been conducted with higher concentrations while physiological concentrations are rather in the picomolar range and may have even beneficial effects[6]. We demonstrate that an 8-residue long peptide (RGTFEGKF), initially designed on the framework GxFxGxF to disrupt sheet-to-sheet packings of Aβ 40 fibrils[27] can target low-n Aβ 42 oligomers (mainly tetramers and hexamers), rather than inhibit Aβ aggregation. Compared to earlier anti-amyloid oligomer strategies, AIP is unique in that this Aβ -oligomer Interacting Peptide (AIP) can “trap” toxic amyloid oligomers—i.e. inhibit the conversion of low-n Aβ 42 oligomers into mature amyloid fibrils, neutralize their toxicity and prevent the growth of Aβ oligomers into larger assemblies
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