|Budget Amount *help
¥3,700,000 (Direct Cost : ¥3,700,000)
Fiscal Year 1999 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1998 : ¥2,300,000 (Direct Cost : ¥2,300,000)
We first examined transgenic mice (Tg) expressing human βAPP695 ΔNL (APPsw mice : Hsiao K et al. Science 1996) to clarify the character of amyloid β protein (Aβ) deposited in brains of these mice. In 8-month-old mice, giant cored plaques (CP) appeared in the hippocampus and the cerebral cortex. Diffuse plaques (DP) and amyloid angiopathy (AA) in some small vessels of cerebral cortex and subaracnoidal space were recognized in 12-month-old mice, and increased with age. These neuropathological structures consisted of various Aβ species with both N-and C- terminal modifications such as those of AD brains. Accumulation of hyperphosphorylated tau as well as _βAPP were observed in dystrophic neurites surrounding CP. Neuronal cell loss as well as synaptic loss were found in cored plaques. The substantial amounts of Aβ40 and Aβ42 in brains at the age of 8 months were detected, and remarkably increased with the evolution of Aβ amyloidosis. Passive avoidance test revealed that these mice have significant memory impairment at the age of 8.5 months. Thus, APPsw mice are useful models for examining the mechanism of AD pathology.
Next, to clarify whether Apolipoprotein E(ApoE) promotes deposition of Aβ in vivo, we examined both brains and plasma of Tg that coexpress APPsw and rat Apo E (corresponding to human ApoE4)((βAPP(+)ApoE(+) Tg). There were no differences in the degree of CP, DP, and AA of between βAPP(+)ApoE(+) Tg and βAPP(+)ApoE(-) Tg at the age of 4 and 8 months. However, at the age of 12 months, degree of CP, DP, and AA in βAPP(+)ApoE(+) Tg was greater than those of βAPP(+)ApoE(-) Tg. The levels of both Aβ40 and Aβ42 in brains of βAPP(+)ApoE(+) Tg were higher than those of βAPP(+)ApoE(-) Tg by 12% and 60%, respectively. Furthermore, the levels of Aβ40 in plasma of βAPP(+)ApoE(+) Tg were also higher than those of βAPP(+)ApoE(-) Tg by 40%. Thus, those findings suggest that ApoE accelerates Aβ deposition by increasing Aβ concentration.