Flemish and Dutch mutations in amyloid β precursor protein have different effects on amyloid β secretion

Mutations in the amyloid β precursor protein (APP) gene cosegregate with autosomal dominant Alzheimer disease (AD). Brain pathology of AD is characterized by amyloid deposition in senile plaques and by neurofibrillary tangles. Amyloid deposits in AD brains consist of amyloid β (Aβ), a 4-kDa proteolytic product of APP. In contrast, two other mutations in APP, the Flemish APP692 and Dutch APP693 mutations, are associated with autosomal dominant cerebral hemorrhages due to congophilic amyloid angiopathy (CAA) in the presence or absence of AD pathology, respectively. Both mutations are located within Aβ near the constitutive cleavage site. While a common effect of AD-linked mutations is to elevate Aβ42 extracellular concentrations, not much is known about the effect of APP692 and APP693. Here we provide evidence that APP692 and APP693 have a different effect on Aβ secretion as determined by cDNA transfaction experiments. While APP692 upregulates both Aβ40 and Aβ42 secretion, APP693 does not. These data corroborate with previous findings that increased Aβ secretion and particularly of Aβ42, is specific for AD pathology.