A NOVEL APP MUTATION ASSOCIATED WITH AN UNUSUAL ALZHEIMER'S DISEASE PATHOLOGY

摘要

The invention relates to the field of Alzheimer's Disease (AD). In particular,the invention provides a novel mutation (T714I) identified in the amyloidprecursor protein (APP), APP714, which leads to a very aggressive form of AD.The mutation involves the 43rd codon of the amyloid .beta. peptide (A.beta.)corresponding to the putative gamma 42-secretase cleavage site. The novelmutation alters both A.beta.40 and A.beta.42 secretion elevating theA.beta.42/A.beta.40 ratio by 10-fold in vitro. Furthermore, the main amyloidplaque pathology in brains of these patients is of the diffuse 'pre-amyloid'type composed primarily of N-truncated A.beta.42. Dense-cored plaques althoughnot absent, were significantly reduced. Also, the usual sites in brain whereA.beta.40 is predominantly deposited, for instance, in vessels as cerebralamyloid angiopathy (CAA) or senile plaque cores, were composed entirely ofA.beta.42 form. Together, these indicate that deposition of N-truncatedA.beta.42 in one of the earliest amyloid deposited in brain, the diffuseplaques, is fully competent of inciting AD either through the well-established'amyloid cascade' or by a yet unknown mechanism(s).