Novel APP mutation associated with an unusual Alzheimers disease pathology

摘要

The invention provides a novel mutation identified in amyloid precursor protein, which leads to a very aggressive form of Alzheimers disease. The mutation involves the 43^rd codon of amyloid peptide (A) corresponding to the putative ₄₂-secretase cleavage site. The novel mutation alters both A₄₀ and A₄₂ secretion elevating the A₄₂/A₄₀ 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 A₄₂. Dense-cored plaques although not absent, were significantly reduced. Also, usual sites in brain where A₄₀ is predominantly deposited, for instance, in vessels such as cerebral amyloid angiopathy or senile plaque cores, were composed entirely of A₄₂ form. Together, these indicate that deposition of N-truncated A₄₂ 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).