Synthetic Aβ peptides acquire prion-like properties in the brain

In transmission studies with Alzheimer's disease (AD) animal models, the formation of A beta plaques is proposed to be initiated by seeding the inoculated amyloid beta (A beta) peptides in the brain. Like the misfolded scrapie prion protein (PrPSc) in prion diseases, A beta in AD shows a certain degree of resistance to protease digestion while the biochemical basis for protease resistance of A beta remains poorly understood. Using in vitro assays, histoblotting, and electron microscopy, we characterize the biochemical and morphological features of synthetic A beta peptides and A beta isolated from AD brain tissues. Consistent with previous observations, monomeric and oligomeric A beta species extracted from AD brains are insoluble in detergent buffers and resistant to digestions with proteinase K (PK). Histoblotting of AD brain tissue sections exhibits an increased A beta immunoreactivity after digestion with PK. In contrast, synthetic A beta 40 and A beta 42 are soluble in detergent buffers and fully digested by PK. Electron microscopy of A beta 40 and A beta 42 synthetic peptides shows that both species of A beta form mature fibrils. Those generated from A beta 40 are longer but less numerous than those made of A beta 42. When spiked into human brain homogenates, both A beta 40 and A beta 42 acquire insolubility in detergent and resistance to PK. Our study favors the hypothesis that the human brain may contain cofactor(s) that confers the synthetic A beta peptides PrPSc-like physicochemical properties.