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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Isotope-labeled amyloid-β does not transmit to the brain in a prion-like manner after peripheral administration
Mirjam Brackhan1,2, Giulio Calza3, Kristiina Lundgren3
1Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway.
Abstract:
Findings of early cerebral amyloid-β deposition in mice after peripheral injection of amyloid-β-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-β aggregates and possibly Alzheimer's disease may be transmissible between individuals. Yet, proof that Aβ 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 13 C-isotope-labeled brain extracts from mice expressing human amyloid-β and track 13 C-lysine-labeled amyloid-β after intraperitoneal administration into young amyloid precursor protein-transgenic mice. We detect injected amyloid-β in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13 C-lysine-labeled amyloid-β is not detectable in the brain whereas the mice incorporate 13 C-lysine from the donor brain extracts into endogenous amyloid-β. Using a highly sensitive and specific proteomic approach, we demonstrate that amyloid-β 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.
Insights
Alzheimer's disease transmission is unlikely. This study found that injected amyloid-beta (Aβ) aggregates do not reach the brain from peripheral sites, refuting transmissibility concerns.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Early cerebral amyloid-beta (Aβ) deposition observed in animal models and human treatments raised concerns about Alzheimer's disease (AD) transmissibility.
- The direct pathway of peripheral Aβ aggregates reaching the brain remained unproven, necessitating investigation into potential transmission routes.
Purpose of the Study:
- To investigate whether peripherally administered amyloid-beta (Aβ) aggregates can reach the brain.
- To determine if Alzheimer's disease (AD) is potentially transmissible between individuals via peripheral exposure to Aβ.
Main Methods:
- Utilized a proteomic approach combining stable isotope labeling (13C-lysine) and targeted mass spectrometry.
- Injected 13C-labeled brain extracts containing human amyloid-beta (Aβ) into amyloid precursor protein-transgenic mice.
- Tracked the presence and incorporation of labeled Aβ in various tissues, including the brain, liver, and lymphoid organs.
Main Results:
- Injected amyloid-beta (Aβ) was detected in the liver and lymphoid tissues for up to 100 days post-injection.
- 13C-labeled Aβ was not detectable in the brain of recipient mice.
- Recipient mice incorporated 13C-lysine from donor brain extracts into their endogenous Aβ, indicating metabolic processing but not direct Aβ transfer.
Conclusions:
- Amyloid-beta (Aβ) does not appear to reach the brain from peripheral administration sites.
- The study provides evidence against the transmissibility of Alzheimer's disease (AD) through peripheral exposure to Aβ aggregates.
- Findings open new research avenues into the mechanisms of protein deposition in neurodegenerative diseases.
