Isotope-labeled amyloid-beta does not transmit to the brain in a prion-like manner after peripheral administration

Findings of early cerebral amyloid-beta deposition in mice after peripheral injection of amyloid-beta-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-beta aggregates and possibly Alzheimer's disease may be transmissible between individuals. Yet, proof that A beta actually reaches the brain from the peripheral injection site is lacking. Here, we use a proteomic approach combining stable isotope labeling of mammals and targeted mass spectrometry. Specifically, we generate C-13-isotope-labeled brain extracts from mice expressing human amyloid-beta and track C-13-lysine-labeled amyloid-beta after intraperitoneal administration into young amyloid precursor protein-transgenic mice. We detect injected amyloid-beta in the liver and lymphoid tissues for up to 100 days. In contrast, injected C-13-lysine-labeled amyloid-beta is not detectable in the brain whereas the mice incorporate C-13-lysine from the donor brain extracts into endogenous amyloid-beta. Using a highly sensitive and specific proteomic approach, we demonstrate that amyloid-beta does not reach the brain from the periphery. Our study argues against potential transmissibility of Alzheimer's disease while opening new avenues to uncover mechanisms of pathophysiological protein deposition.