Racemization: its biological significance on neuropathogenesis of Alzheimer's disease

Amyloid beta protein (A beta) 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 A beta, we synthesized three kinds of A beta peptides in which D-Asp was substituted for L-Asp residues, i.e, normal A beta 1-40, [D-Asp7]A beta 1-40 and [D-Asp23]A beta 1-40. The aggregation and fibril formation of each peptide was examined by means of spectrofluorometry and electron microscopy. Of the three peptides, normal A beta showed the gradual increase of aggregation while [D-Asp7]A beta 1-40 and [D-Asp23] A beta 1-40 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 A beta antibody and anti-A beta 1-42/43 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 A beta (A beta 1-42/43). Taken together with the recent accumulated evidence on the aggregation mechanisms of A beta, the data presented here suggest that racemization may occur after the amyloid fibril formation but enhance the aggregation process by shifting the equilibrium of A beta from the soluble form to the insoluble form in Alzheimer's disease.