Mapping post-translational modifications across amyloid-β deposits in Alzheimer’s disease: A neuropathologic survey with in vitro functional analysis of nitration
Abstract
Background Amyloid-β (Aβ) pathology in Alzheimer’s disease (AD) includes distinct types of plaques and cerebral amyloid angiopathy (CAA). Post-translational modifications (PTMs) may define Aβ deposit-specific signatures. Among them, nitration of tyrosine-10 (3′-nitrotyrosine, 3-NT) links oxidative stress to Aβ modification and microglial activation, but its spatial distribution across deposit types and impact on aggregation dynamics remain unclear. Methods Parietal cortex tissue from AD and CAA cases (n = 19) and controls (n = 9) was analyzed by multiplex immunofluorescence for Aβ species (Aβaa1-8, AβN3pE, pSer8-Aβ), 3-NT, thioflavin-S, and CD68. Distinct deposits, including diffuse plaques (n = 70) classic cored plaques (n = 70), coarse-grained plaques (n = 40), capillary CAA (capCAA; n = 80), larger vessel CAA (n = 80), and leptomeningeal CAA (n = 25) were annotated, together with gray matter regions from control tissue lacking Aβ pathology (n = 90). In vitro assays evaluated how 3-NT affects Aβ aggregation kinetics, microglial morphology, and neuronal viability. Results We observed Aβ deposit-specific PTM signatures. Classic cored and coarse-grained plaques contained increased pyroglutamylated (Aβ N3pE ) and phosphorylated (pSer8-Aβ) species compared to diffuse plaques. In contrast, 3-NT showed a distinct vascular predilection, with the highest relative burden in larger vessel and leptomeningeal CAA. 3-NT colocalized with β-sheet–rich thioflavin-S-positive fibrils and areas of CD68-positive microglia. In vitro, nitration slowed oligomer-to-fibril conversion but accelerated the growth of pre-formed fibrils and sustained microglial activation without increasing neuronal toxicity. Conclusions Distinct PTMs delineate the compartment-specific architectural signatures of Aβ deposits. Whereas AβN3pE and pSer8-Aβ broadly label parenchymal plaques, 3-NT shows a vascular predilection, particularly in leptomeningeal CAA. This compartmentalized pattern identifies nitration as a candidate marker of vascular Aβ pathology and a possible risk indicator for amyloid-related imaging abnormalities (ARIA) during anti-Aβ immunotherapy.
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BibTeX
@misc{basile2026mapping,
title = {{Mapping post-translational modifications across amyloid-β deposits in Alzheimer’s disease: A neuropathologic survey with in vitro functional analysis of nitration}},
author = {Sarah Basile and Fleur Schipper and Stefania Zimbone and Sanne M.M. Vermorgen and Francesco Bellia and Cristina Parisi and Salvatore Sortino and Jochen Walter and Maria Laura Giuffrida and Annemiek J.M. Rozemuller and Jeroen J.M. Hoozemans and Agata Copani and Baayla D.C. Boon},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-10769225/v1},
url = {https://doi.org/10.21203/rs.3.rs-10769225/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Mapping post-translational modifications across amyloid-β deposits in Alzheimer’s disease: A neuropathologic survey with in vitro functional analysis of nitration
AU - Sarah Basile
AU - Fleur Schipper
AU - Stefania Zimbone
AU - Sanne M.M. Vermorgen
AU - Francesco Bellia
AU - Cristina Parisi
AU - Salvatore Sortino
AU - Jochen Walter
AU - Maria Laura Giuffrida
AU - Annemiek J.M. Rozemuller
AU - Jeroen J.M. Hoozemans
AU - Agata Copani
AU - Baayla D.C. Boon
PY - 2026
DA - 2026/10/18
PB - Research Square
DO - 10.21203/rs.3.rs-10769225/v1
UR - https://doi.org/10.21203/rs.3.rs-10769225/v1
AB - Background Amyloid-β (Aβ) pathology in Alzheimer’s disease (AD) includes distinct types of plaques and cerebral amyloid angiopathy (CAA). Post-translational modifications (PTMs) may define Aβ deposit-specific signatures. Among them, nitration of tyrosine-10 (3′-nitrotyrosine, 3-NT) links oxidative stress to Aβ modification and microglial activation, but its spatial distribution across deposit types and impact on aggregation dynamics remain unclear. Methods Parietal cortex tissue from AD and CAA cases (n = 19) and controls (n = 9) was analyzed by multiplex immunofluorescence for Aβ species (Aβaa1-8, AβN3pE, pSer8-Aβ), 3-NT, thioflavin-S, and CD68. Distinct deposits, including diffuse plaques (n = 70) classic cored plaques (n = 70), coarse-grained plaques (n = 40), capillary CAA (capCAA; n = 80), larger vessel CAA (n = 80), and leptomeningeal CAA (n = 25) were annotated, together with gray matter regions from control tissue lacking Aβ pathology (n = 90). In vitro assays evaluated how 3-NT affects Aβ aggregation kinetics, microglial morphology, and neuronal viability. Results We observed Aβ deposit-specific PTM signatures. Classic cored and coarse-grained plaques contained increased pyroglutamylated (Aβ N3pE ) and phosphorylated (pSer8-Aβ) species compared to diffuse plaques. In contrast, 3-NT showed a distinct vascular predilection, with the highest relative burden in larger vessel and leptomeningeal CAA. 3-NT colocalized with β-sheet–rich thioflavin-S-positive fibrils and areas of CD68-positive microglia. In vitro, nitration slowed oligomer-to-fibril conversion but accelerated the growth of pre-formed fibrils and sustained microglial activation without increasing neuronal toxicity. Conclusions Distinct PTMs delineate the compartment-specific architectural signatures of Aβ deposits. Whereas AβN3pE and pSer8-Aβ broadly label parenchymal plaques, 3-NT shows a vascular predilection, particularly in leptomeningeal CAA. This compartmentalized pattern identifies nitration as a candidate marker of vascular Aβ pathology and a possible risk indicator for amyloid-related imaging abnormalities (ARIA) during anti-Aβ immunotherapy.
SN - 2693-5015
ER -