| First Author | Roos TT | Year | 2021 |
| Journal | Acta Neuropathol | Volume | 142 |
| Issue | 4 | Pages | 669-687 |
| PubMed ID | 34272583 | Mgi Jnum | J:350898 |
| Mgi Id | MGI:7664260 | Doi | 10.1007/s00401-021-02345-9 |
| Citation | Roos TT, et al. (2021) Neuronal spreading and plaque induction of intracellular Abeta and its disruption of Abeta homeostasis. Acta Neuropathol 142(4):669-687 |
| abstractText | The amyloid-beta peptide (Abeta) 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 Abeta in its prion-like spread. We demonstrate that an intracellular source of Abeta 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 Abeta 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 Abeta leads to an apparent redistribution of Abeta 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 Abeta disturbs homeostatic control of Abeta levels and can contribute to the up to 10,000-fold increase of Abeta in the AD brain. Our data indicate an essential role for intracellular prion-like Abeta and its synaptic spread in the pathogenesis of AD. |
