Characterization of amyloid beta protein species in the plasma, cerebrospinal fluid and brains of patients with Alzheimer's disease

Abstract

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