Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/s40478-018-0529-x
Keywords
A beta; Amyloid; Prion; like transmission; Propagation; Knock-in mice; Cerebral amyloid angiopathy; Amyloid precursor protein
Categories
Funding
- Canadian Institutes of Health Research [MOP-136899]
- Alzheimer Society Canada/Brain Canada [16-13]
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The amyloid cascade hypothesis posits that the initiating event in Alzheimer's disease (AD) is the aggregation and deposition of the beta-amyloid (A beta) peptide, which is a proteolytic cleavage product of the amyloid precursor protein (APP). Mounting evidence suggests that the formation and spread of prion-like A beta aggregates during AD may contribute to disease progression. Inoculation of transgenic mice that overexpress APP with pre-formed A beta aggregates results in the prion-like induction of cerebral A beta deposition. To determine whether A beta deposition can also be induced when physiological APP levels are present in the brain, we inoculated AppNL-F mice, a knock-in model of AD that avoids potential artifacts associated with APP overexpression, with A beta aggregates derived from the brains of AD patients or transgenic mice. In all cases, induced A beta deposition was apparent in the corpus callosum, olfactory bulb, and meningeal blood vessels of inoculated mice at 130-150 days post-inoculation, whereas uninoculated and bufferinoculated animals exhibited minimal or no A beta deposits at these ages. Interestingly, despite being predominantly composed of protease-resistant A beta 42 aggregates, the induced parenchymal A beta deposits were largely diffuse and were unreactive to an amyloid-binding dye. These results demonstrate that APP overexpression is not a prerequisite for the prion-like induction of cerebral A beta deposition. Accordingly, spreading of A beta deposition may contribute to disease progression in AD patients.
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