Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid β-protein (Aβ), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two Aβ variants, we used an in vivo paradigm in which freshly solubilized Aβ1-40 or Aβ1-42 was injected into rat brains, followed by examination using Congo red birefringence, Aβ immunohistochemistry, and electron microscopy. In the rat brain, soluble Aβ1-40 and Aβ1-42 formed aggregates, and the Aβ1-40 but not the Aβ1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the Aβ1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the Aβ1-42 aggregates contained nonfibrillar amorphous material. Preincubation of Aβ1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated Aβ1-42, the aggregates remained birefringent in the rat brain. Thus, a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble Aβ1-42. To analyze the postsecretory processing of Aβ, we used the same in vivo paradigm and showed that Aβ1-40 and Aβ1-42 were processed at their N termini to yield variants starting at pyroglutamate, and at their C termini to yield variants ending at Val40 and at Val39. Thus the normal rat bran could produce enzymes that mediate the conversion of Aβ1- 40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of Aβ deposition evolving into amyloid plaques in AD.
|ジャーナル||Journal of Neuroscience|
|出版ステータス||Published - 1997|
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