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Repeated electromagnetic field stimulation lowers amyloid-? peptide levels in primary human mixed brain tissue cultures.

ABSTRACT: Late Onset Alzheimer's Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-? (A?) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic A? levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on A? levels (A?40 and A?42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted A?40 (p = 001) and A?42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower A? levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in A?40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted A? precursor protein-? (sAPP?) levels, suggesting the decrease in A? did not likely result from redirection toward the ?-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate A? deposition.

SUBMITTER: Perez FP

PROVIDER: S-EPMC7804462 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures.

Perez Felipe P FP Maloney Bryan B Chopra Nipun N Morisaki Jorge J JJ Lahiri Debomoy K DK

Scientific reports 20210112 1

Late Onset Alzheimer's Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues i ...[more]

PMID: 33436686

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Project description:The amyloid beta (Aβ) peptide represents a 37 to 49 amino acids endoproteolytic fragment of the amyloid precursor protein. The cellular biology that governs the formation and clearance of Aβ has been understood to play a critical role in Alzheimer’s disease (AD). The primary objective of this study was to generate an in-depth inventory of human brain proteins that oligomeric preparations of Aβ1-42 can bind to using an unbiased in vitro discovery approach. Synthetic Aβ1-42 peptides and a brain extract generated from adult human frontal lobe tissue served in these studies as baits and biological source material, respectively. oAβ1-42 was prepared by aggregating the peptide at 4 ºC for 24 h, using previously described procedures known to generate amyloid-β-derived diffusible ligands (ADDLs). Because the interaction with a given binding partner may rely on a binding epitope that comprises N- or C-terminal residues of Aβ1-42, two separate experiments (I and II) were conducted, which differed in the orientation the oAβ1-42 bait was tethered to the affinity matrix. To facilitate meaningful comparisons across experiments, the method of Aβ1-42 capture was not based on immunoaffinity reagents. Instead, alternative Aβ1-42 baits were equipped with biotin moieties attached to the N- or C-terminus by a 6-carbon linker chain, enabling their consistent affinity-capture on streptavidin agarose matrices. Biotin-saturated streptavidin agarose matrices served as negative controls and three biological replicates of samples and controls were generated for each of the three separate interactome datasets by reproducing the affinity-capture step side-by-side on three separate streptavidin agarose affinity matrices that had been saturated with the biotinylated baits. To identify differences in protein-protein interactions of monomeric versus oligomeric Aβ1-42, a 3rd interactome experiment was conducted in which oAβ1-42-biotin or mAβ1-42-biotin served as baits. Digitonin-solubilized brain extracts, which are known to comprise extracellular and most cellular proteins (except for nuclear proteins) served as biological starting material, consistent with the main subcellular areas previously reported to harbor Aβ. Following extensive washes of affinity matrices in their protein-bound state, binders to the bait peptides were eluted by rapid acidification, fully denatured in 9 M urea, and trypsinized. To avoid notorious confounders related to variances in the subsequent handling and analysis of samples, individual peptide mixtures were labeled with distinct isobaric tandem mass tags (TMT) in a six-plex format, then combined and concomitantly subjected to ZipTip-based pre-analysis clean-up by strong cation exchange (SCX) and reversed phase (RP) separation. Four-hour split-free reversed phase nanospray separations were online coupled to an Orbitrap Fusion Tribrid mass spectrometer, which was configured to run an MS3 analysis method.

Dataset Information

Repeated electromagnetic field stimulation lowers amyloid-? peptide levels in primary human mixed brain tissue cultures.

Publications

Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures.

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