Journal
EMBO REPORTS
Volume 23, Issue 7, Pages -Publisher
WILEY
DOI: 10.15252/embr.202154405
Keywords
Alzheimer's disease; brain; multiple reaction monitoring immuno-mass spectrometry; prion-like; seeding
Categories
Funding
- Deutsche Forschungsgemeinschaft/Germany [DFG 263024513]
- HelseSO/Norway [2019-054, 2019-055, 2022-046]
- Norges forskningsrad/Norway [251290, 295910, 327571]
- EEA grant/Norway [TAR TARIMAD TO100078]
- AKA - Finland [301228, 318857]
- BMBF - Germany [01ED1605, 01ED2106]
- CSO-MOH - Israel [30000-12631]
- NFR - Norway [327571, 260786]
- SRC - Sweden [2015-06795, 2020-02905]
- FFG - Austria [882717]
- MSMT - Czech Republic [8F21002]
- VIAA - Latvia [ES RTD/2020/26]
- ANR - France [20-JPW2-0002-04]
- European Union's Horizon 2020 research and innovation program [643417]
- ERA-NET NEURON (ERA-NET MicroSynDep project)
- Svenska Sallskapet for Medicinsk Forskning (SSMF) [P17-0047]
- Svenska Forskningsradet (Formas) [2020-01013]
- Ake Wiberg stiftelse [M20-0148]
- Alzheimerfonden [AF-968052]
- Petrus och Augusta Hedlunds stiftelse [M-2020-1313]
- Foundation for Geriatric Diseases at Karolinska Instititet [2020-2267]
- Ahlen-stiftelsen [203087]
- Swedish Research Council [2020-02905] Funding Source: Swedish Research Council
- Formas [2020-01013] Funding Source: Formas
- Academy of Finland (AKA) [318857] Funding Source: Academy of Finland (AKA)
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Using stable isotope labeling and targeted mass spectrometry, the study shows that amyloid-beta does not reach the brain from the periphery, contradicting the theory of transmissibility in Alzheimer's disease.
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.
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