Highly potent soluble amyloid-β seeds in human Alzheimer brain but not cerebrospinal fluid

The soluble fraction of brain samples from patients with Alzheimer's disease contains highly biologically active amyloid-beta seeds. In this study, we sought to assess the potency of soluble amyloid-beta seeds derived from the brain and cerebrospinal fluid. Soluble Alzheimer's disease brain extracts were serially diluted and then injected into the hippocampus of young, APP transgenic mice. Eight months later, seeded amyloid-beta deposition was evident even when the hippocampus received subattomole amounts of brain-derived amyloid-beta. In contrast, cerebrospinal fluid from patients with Alzheimer's disease, which contained more than 10-fold higher levels of amyloid-beta peptide than the most concentrated soluble brain extracts, did not induce detectable seeding activity in vivo. Similarly, cerebrospinal fluid from aged APP-transgenic donor mice failed to induce cerebral amyloid-beta deposition. In comparison to the soluble brain fraction, cerebrospinal fluid largely lacked N-terminally truncated amyloid-beta species and exhibited smaller amyloid-beta-positive particles, features that may contribute to the lack of in vivo seeding by cerebrospinal fluid. Interestingly, the same cerebrospinal fluid showed at least some seeding activity in an in vitro assay. The present results indicate that the biological seeding activity of soluble amyloid-beta species is orders of magnitude greater in brain extracts than in the cerebrospinal fluid.