1998 Volume 35 Issue 4 Pages 273-277
Extracellular deposition of amyloid β protein (Aβ) as senile plaques and cerebral amyloid angiopathy (CAA) is one of the essential pathological characteristics of Alzheimer's disease (AD). Several Aβ species with different carboxyl termini, including Aβ42 (43) and Aβ40 ending at residue 42 (43) and 40, respectively, have been identified in CAA and in senile plaque cores. Because Aβ42 (43), the major component of diffuse plaque which is the earliest pathological change in AD brains, forms insoluble amyloid fibrils more rapidly than does Aβ40, it has been hypothesized that Aβ42 (43) plays a role in amyloid seeding and Aβ40, in the elongation of amyloid fibrils on a seed of Aβ42 (43).
We used enzyme-linked immunosorbent assay (ELISA) with site-specific monoclonal antibodies to differentiate Aβ42 (43) from Aβ40. First, we measured the amounts of different Aβ species in plasma from patients with sporadic probable AD, age-matched patients with neurologic diseases but without dementia, and age-matched normal controls. Concentrations of Aβ1-40 and Aβ1-42 (43) in plasma did not differ significantly among the three groups. Second, CSF levels of Aβ species (CSF-Aβ) with different carboxy termini, i.e., AβX-40 and AβX-42 (43) as well as Aβ1-40 and Aβ1-42 (43), were measured in patients with AD and in age-matched controls without dementia using ELISA. Levels of both CSF-AβX-42 (43) and Aβ1-42 (43) were significantly lower in the patients with AD that in the controls, but neither the levels of CSF-AβX-40 nor those of CSF-Aβ1-40 differed between the two groups, which suggest that increased adsorption of Aβ42 (43) to Aβ deposition in AD brains, decreased secretion of Aβ42 (43) in CSF, or increased clearance of Aβ42 (43) from CSF might explain the low levels of Aβ42 (43) in the CSF of patients with AD. Third, we measured the concentrations of various Aβ species post-mortem in the cerebral cortex of patients with PS-1 mutations and β amyloid precursor protein (APP) 717 mutation linked to familial AD or Down syndrome. The results indicate that one effect of PS-1 mutations, APP717 mutation and Down syndrome is to cause dramatic and accelerated accumulation of Aβ42 (43) in the brain as compared with sporadic AD. In particular, the increases in Aβ1-42 (43) showed a crude inverse correlation with the age of onset in each subtype of AD.
Thus, quantitative studies differentiating Aβ42 (43) from Aβ40 have established the fundamental importance of Aβ42 (43) in AD.
