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Volume 17, Number 21, Issue of November 1, 1997 pp. 8187-8193
Copyright ©1997 Society for Neuroscience

Amyloid -Protein (A) 1-40 But Not A1-42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

Received June 26, 1997; revised Aug. 13, 1997; accepted Aug. 20, 1997.

Ryong-Woon Shin¹, Koichi Ogino², Akira Kondo³, Takaomi C. Saido⁴, John Q. Trojanowski⁵, Tetsuyuki Kitamoto¹, and Jun Tateishi⁶

¹ Department of Neurological Science, Tohoku University School of Medicine, Sendai 980, Japan, ² Cellular Technology Institute, Otsuka Pharmaceutical Co., Tokushima 771-01, Japan, ³ Department of Neurology, Koga General Hospital, Miyazaki 880, Japan, ⁴ Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113, Japan, ⁵ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, and ⁶ Department of Neuropathology, Neurological Institute, Kyushu University School of Medicine, Fukuoka 812-82, Japan

Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid -protein (A), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two A variants, we used an in vivo paradigm in which freshly solubilized A1-40 or A1-42 was injected into rat brains, followed by examination using Congo red birefringence, A immunohistochemistry, and electron microscopy. In the rat brain, soluble A 1-40 and A1-42 formed aggregates, and the A1-40 but not the A1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the A1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the A1-42 aggregates contained nonfibrillar amorphous material. Preincubation of A1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated A1-42, 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 A1-42. To analyze the postsecretory processing of A, we used the same in vivo paradigm and showed that A1-40 and A1-42 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 brain could produce enzymes that mediate the conversion of A 1-40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of A deposition evolving into amyloid plaques in AD.

Key words: Alzheimer disease; senile plaques; amyloid -protein; amyloid fibrils; in vivo; in vitro

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