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

The amyloid-beta peptide (A beta) 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 A beta in its prion-like spread. We demonstrate that an intracellular source of A beta 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 A beta 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 A beta leads to an apparent redistribution of A beta 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 A beta disturbs homeostatic control of A beta levels and can contribute to the up to 10,000-fold increase of A beta in the AD brain. Our data indicate an essential role for intracellular prion-like A beta and its synaptic spread in the pathogenesis of AD.

Automated summary

Research suggests that intracellular A beta plays a crucial role in the prion-like spread of Alzheimer's disease, leading to plaque formation and neuronal damage.