Aβ-42 Side Chain Deamidation at Q15 or N27 Modulates Protein Aggregation and Alters Microglial Cytokines and CD68.
9 affiliations
- 1George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia30332, United States.
- 2School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia30332, United States.
- 3Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia30332, United States.
- 4School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia30332, United States.
- 5Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California95064, United States.
- 6T-NeuroDx, Albuquerque, New Mexico87123, United States.
- 7StemVax Therapeutics, a NovAccess Global Company, Chagrin Falls, Ohio44023, United States.
- 8World Brain Mapping Foundation, Society for Brain Mapping & Therapeutics, Pacific Palisades, California90272-3668, United States.
- 9Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia30332, United States.
Abstract
The progressive aggregation of amyloid beta (Aβ) monomers into oligomers is a critical factor in Alzheimer's disease (AD) pathogenesis. Although mutated forms of Aβ have been shown to display altered aggregation dynamics, the specific effects of deamidated Aβ on microglial function remain understudied. Our research group previously found that the deamidated variant Aβ-42-N27D modified Aβ aggregation, reduced neurotoxicity, and reduced microglial reactivity, but the impact of Aβ-42 side chain deamidation in general on such parameters remained unclear. Here, we expanded on our prior work by investigating how two site-specific Aβ-42 mutations (Q15E & N27D), where neutral amide side chains are replaced with negatively charged carboxylic acids, affect aggregation and microglial immune response using a mouse microglial cell line. Size exclusion chromatography, Thioflavin T fluorescence, circular dichroism, and dynamic light scattering revealed that Aβ-42-Q15E and Aβ-42-N27D exhibit reduced aggregation compared to Aβ-42 wild type (WT). Multiplexed analysis of 8 microglial cytokines secreted into the culture medium revealed that Aβ-42-Q15E and Aβ-42-N27D decrease the expression of inflammatory cytokines such as IL-6, IP-10, and MIP-1α relative to Aβ-42-WT. Immunocytochemistry revealed that Aβ-42-Q15E and Aβ-42-N27D decrease CD68 expression and intracellular Aβ labeling relative to Aβ-42-WT. These findings demonstrate that deamidation significantly alters Aβ-42 aggregation and microglial activation, suggesting structural modifications to Aβ-42 modulate inflammatory signaling in AD. This work provides a foundation for future studies on Aβ-42 post-translational modifications as potential therapeutic targets in AD.
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BibTeX
@article{griffin2026aβ42,
title = {{Aβ-42 Side Chain Deamidation at Q15 or N27 Modulates Protein Aggregation and Alters Microglial Cytokines and CD68.}},
author = {Martin N Griffin and Daniel M Dinakarapandian and Chenxing Li and Pranay Ramaswamy and Sia J Saheba and Janie Lee and Tarunya Rao Sudarshan and Maria Sajimon and Christopher J Wheeler and Jevgenij A Raskatov and Anant K Paravastu and Levi B Wood},
journal = {ACS chemical neuroscience},
year = {2026},
month = oct,
doi = {10.1021/acschemneuro.6c00024},
url = {https://europepmc.org/article/MED/42904641},
note = {CC BY},
}
RIS
TY - JOUR
TI - Aβ-42 Side Chain Deamidation at Q15 or N27 Modulates Protein Aggregation and Alters Microglial Cytokines and CD68.
AU - Martin N Griffin
AU - Daniel M Dinakarapandian
AU - Chenxing Li
AU - Pranay Ramaswamy
AU - Sia J Saheba
AU - Janie Lee
AU - Tarunya Rao Sudarshan
AU - Maria Sajimon
AU - Christopher J Wheeler
AU - Jevgenij A Raskatov
AU - Anant K Paravastu
AU - Levi B Wood
PY - 2026
DA - 2026/10/01
JO - ACS chemical neuroscience
DO - 10.1021/acschemneuro.6c00024
UR - https://europepmc.org/article/MED/42904641
AB - The progressive aggregation of amyloid beta (Aβ) monomers into oligomers is a critical factor in Alzheimer's disease (AD) pathogenesis. Although mutated forms of Aβ have been shown to display altered aggregation dynamics, the specific effects of deamidated Aβ on microglial function remain understudied. Our research group previously found that the deamidated variant Aβ-42-N27D modified Aβ aggregation, reduced neurotoxicity, and reduced microglial reactivity, but the impact of Aβ-42 side chain deamidation in general on such parameters remained unclear. Here, we expanded on our prior work by investigating how two site-specific Aβ-42 mutations (Q15E & N27D), where neutral amide side chains are replaced with negatively charged carboxylic acids, affect aggregation and microglial immune response using a mouse microglial cell line. Size exclusion chromatography, Thioflavin T fluorescence, circular dichroism, and dynamic light scattering revealed that Aβ-42-Q15E and Aβ-42-N27D exhibit reduced aggregation compared to Aβ-42 wild type (WT). Multiplexed analysis of 8 microglial cytokines secreted into the culture medium revealed that Aβ-42-Q15E and Aβ-42-N27D decrease the expression of inflammatory cytokines such as IL-6, IP-10, and MIP-1α relative to Aβ-42-WT. Immunocytochemistry revealed that Aβ-42-Q15E and Aβ-42-N27D decrease CD68 expression and intracellular Aβ labeling relative to Aβ-42-WT. These findings demonstrate that deamidation significantly alters Aβ-42 aggregation and microglial activation, suggesting structural modifications to Aβ-42 modulate inflammatory signaling in AD. This work provides a foundation for future studies on Aβ-42 post-translational modifications as potential therapeutic targets in AD.
SN - 1948-7193
ER -