Novel APP mutation associated with an unusual Alzheimer's disease pathology

Abstract

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 β peptide (Aβ) corresponding to the putative γ42-secretase cleavage site. The novel mutation alters both Aβ40 and Aβ42 secretion elevating the Aβ42/Aβ40 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 Aβ42. Dense-cored plaques although not absent, were significantly reduced. Also, usual sites in brain where Aβ40 is predominantly deposited, for instance, in vessels such as cerebral amyloid angiopathy or senile plaque cores, were composed entirely of Aβ42 form. Together, these indicate that deposition of N-truncated Aβ42 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).

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