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Amyloid pathology and synaptic loss in pathological aging

Gkanatsiou, E; Nilsson, J; Toomey, CE; Vrillon, A; Kvartsberg, H; Portelius, E; Zetterberg, H; ... Brinkmalm, G; + view all (2021) Amyloid pathology and synaptic loss in pathological aging. Journal of Neurochemistry 10.1111/jnc.15487. (In press). Green open access

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Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory dysfunction and cognitive decline. Pathological aging (PA) describes patients who are amyloid-positive but cognitively unimpaired at time of death. Both AD and PA contain amyloid plaques dominated by amyloid β (Aβ) peptides. In this study, we investigated and compared synaptic protein levels, amyloid plaque load, and Aβ peptide patterns between AD and PA. Two cohorts of post-mortem brain tissue were investigated. In the first, consisting of controls, PA, AD, and familial AD (FAD) individuals, synaptic proteins extracted with tris(hydroxymethyl)aminomethane-buffered saline (TBS) were analyzed. In the second, consisting of tissue from AD and PA patients from three different regions (occipital lobe, frontal lobe, and cerebellum), a two-step extraction was performed. Five synaptic proteins were extracted using TBS, and from the remaining portion Aβ peptides were extracted using formic acid. Subsequently, immunoprecipitation with several antibodies targeting different proteins/peptides was performed for both fractions, which were subsequently analyzed by mass spectrometry. The levels of synaptic proteins were lower in AD (and FAD) compared with PA (and controls), confirming synaptic loss in AD patients. The amyloid plaque load was increased in AD compared with PA, and the relative amount of Aβ40 was higher in AD while for Aβ42 it was higher in PA. In AD loss of synaptic function was associated with increased plaque load and increased amounts of Aβ40 compared with PA cases, suggesting that synaptic function is preserved in PA cases even in the presence of Aβ.

Type: Article
Title: Amyloid pathology and synaptic loss in pathological aging
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/jnc.15487
Publisher version: http://dx.doi.org/10.1111/jnc.15487
Language: English
Additional information: © 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: Alzheimer's disease, amyloid beta, immunoprecipitation, mass spectrometry, pathological aging, RBM3, SNAP-25, synaptophysin, synaptotagmin-1, synaptotagmin-7
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10134350
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