| 摘要 |
The invention provides a novel mutation identified in amyloid precursor protein, which leads to a very aggressive form of Alzheimer's disease. The mutation involves the 43rd codon of amyloid beta peptide (Abeta) corresponding to the putative gamma42-secretase cleavage site. The novel mutation alters both Abeta40 and Abeta42 secretion elevating the Abeta42/Abeta40 ratio by 10-fold in vitro. Furthermore, the main amyloid plaque pathology in brains of these patients is of the diffuse "pre-amyloid' type composed primarily of N-truncated Abeta42. Dense-cored plaques although not absent, were significantly reduced. Also, usual sites in brain where Abeta40 is predominantly deposited, for instance, in vessels such as cerebral amyloid angiopathy or senile plaque cores, were composed entirely of Abeta42 form. Together, these indicate that deposition of N-truncated Abeta42 in one of the earliest amyloid deposited in brain, the diffuse plaques, is fully competent of inciting AD through the well-established "amyloid cascade' or by yet unknown mechanism(s). |
