Prion-like propagation of ?-amyloid aggregates in the absence of APP overexpression.

ABSTRACT: The amyloid cascade hypothesis posits that the initiating event in Alzheimer's disease (AD) is the aggregation and deposition of the ?-amyloid (A?) 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? aggregates during AD may contribute to disease progression. Inoculation of transgenic mice that overexpress APP with pre-formed A? aggregates results in the prion-like induction of cerebral A? deposition. To determine whether A? 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? aggregates derived from the brains of AD patients or transgenic mice. In all cases, induced A? 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 buffer-inoculated animals exhibited minimal or no A? deposits at these ages. Interestingly, despite being predominantly composed of protease-resistant A?42 aggregates, the induced parenchymal A? 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? deposition. Accordingly, spreading of A? deposition may contribute to disease progression in AD patients.

SUBMITTER: Ruiz-Riquelme A 

PROVIDER: S-EPMC5883524 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature