Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life.

Nature Neuroscience
Ruth E UhlmannMathias Jucker

Abstract

Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer's disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease-currently defined as Aβ deposition without clinical symptoms-may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.

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Citations

Feb 8, 2021·Biochimica Et Biophysica Acta. Molecular Cell Research·April L Darling, James Shorter
Feb 16, 2021·Acta Neuropathologica·Nicholas J AshtonKaj Blennow
Apr 30, 2021·Nature·Sandro Da MesquitaJonathan Kipnis
May 12, 2021·Acta Neuropathologica Communications·Alejandro Ruiz-RiquelmeJoel C Watts
Sep 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·Yuechuan XuPeter G Vekilov
Sep 23, 2021·Nature Reviews. Neurology·Eric McDadeStefan F Lichtenthaler

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Methods Mentioned

BETA
electrophoresis
immunoprecipitation
pull down
transgenic
imaging techniques
X-ray
enzyme-linked immunosorbent assay
Assay

Software Mentioned

Stereo Investigator
GraphPad
BioRender
Prism
Excel
ImageJ
cmAducanumab
Xstella
cmAdu
MSD DISCOVERY WORKBENCH

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