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

Springer Science and Business Media LLC - Tập 142 - Trang 669-687 - 2021
Tomas T. Roos1, Megg G. Garcia1,2, Isak Martinsson1, Rana Mabrouk3, Bodil Israelsson1, Tomas Deierborg2, Asgeir Kobro-Flatmoen4, Heikki Tanila3, Gunnar K. Gouras1
1Experimental Dementia Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
2Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden
3A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland
4Kavli Institute for Systems Neuroscience, Trondheim, Norway

Tóm tắt

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.

Tài liệu tham khảo

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