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Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis

Roos, Tomas T LU ; Garcia, Megg G LU orcid ; Martinsson, Isak LU ; Mabrouk, Rana ; Israelsson, Bodil LU ; Deierborg, Tomas LU ; Kobro-Flatmoen, Asgeir ; Tanila, Heikki and Gouras, Gunnar K LU orcid (2021) In Acta Neuropathologica 142(4). p.669-687
Abstract

The amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer's disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an... (More)

The amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer's disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, Amyloid, Entorhinal cortex, Hippocampus, Interneurons, Prion-like
in
Acta Neuropathologica
volume
142
issue
4
pages
669 - 687
publisher
Springer
external identifiers
  • pmid:34272583
  • scopus:85110397974
ISSN
1432-0533
DOI
10.1007/s00401-021-02345-9
project
Neuroinflammation and amyloid-β in early Alzheimer’s disease: Insight into the earliest events using mouse models
language
English
LU publication?
yes
id
09636738-078b-47e9-872f-a66c1b689102
date added to LUP
2021-07-26 14:36:54
date last changed
2024-06-15 13:44:59
@article{09636738-078b-47e9-872f-a66c1b689102,
  abstract     = {{<p>The amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer's disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.</p>}},
  author       = {{Roos, Tomas T and Garcia, Megg G and Martinsson, Isak and Mabrouk, Rana and Israelsson, Bodil and Deierborg, Tomas and Kobro-Flatmoen, Asgeir and Tanila, Heikki and Gouras, Gunnar K}},
  issn         = {{1432-0533}},
  keywords     = {{Alzheimer’s disease; Amyloid; Entorhinal cortex; Hippocampus; Interneurons; Prion-like}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{4}},
  pages        = {{669--687}},
  publisher    = {{Springer}},
  series       = {{Acta Neuropathologica}},
  title        = {{Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis}},
  url          = {{http://dx.doi.org/10.1007/s00401-021-02345-9}},
  doi          = {{10.1007/s00401-021-02345-9}},
  volume       = {{142}},
  year         = {{2021}},
}