1994 Volume 174 Issue 3 Pages 251-262
MORI, H., ISHII, K., TOMIYAMA, T., FURIYA, Y., SAHARA, N., ASANO, S., ENDO, N., SHIRASAWA, T. and TAKIO, K. Racemization: Its Biological Significance in Neuropathogenesis of Alzheimer's Disease. Tohoku J. Exp. Med., 1994, 174 (3), 251-262 - Amyloid β protein (Aβ) in neuritic plaques of Alzheimer's disease has been found to be racemized and/or isomerized at their Asp residues. To elucidate the effect of racemization on the aggregation properties of Aβ, we synthesized three kinds of Aβ peptides in which D-Asp was substituted for L-Asp residues, i.e, normal Aβ1-40, [D-Asp7] Aβ1-40 and [D-Asp23] Aβ1-40. The aggregation and fibril formation of each peptide was examined by means of spectrofluorometry and electron microscopy. Of the three peptides, normal Aβ showed the gradual increase of aggregation while [D-Asp7] Aβ1-40 and [D-Asp23] Aβ1-40 showed more enhanced aggregation at the final stage when the fibril formations were detected in all peptides solutions by electron microscopy. A comparative immunohistochemical study by anti-racemized Aβ antibody and anti-Aβ1-42/43 antibody further showed the in vivo incorporation of D-Asp in senile plaques of Alzheimer's disease brains, which may be involved in plaque formation at the later stage than the deposition of the longer form of Aβ (Aβ1-42/43). Taken together with the recent accumulated evidence on the aggregation mechanisms of Aβ, the data presented here suggest that racemization may occur after the amyloid fibril formation but enhance the aggregation process by shifting the equilibrium of Aβ from the soluble form to the insoluble form in Alzheimer's disease.
