THE E280A PRESENILIN-1 ALZHEIMER MUTATION PRODUCES INCREASED A-BETA-42 DEPOSITION AND SEVERE CEREBELLAR PATHOLOGY

Missense mutations in the presenilin 1 (PS1) gene cause the most commo n form of dominant early-onset familial Alzheimer's disease (FAD)(1,2) and are associated with increased levels of amyloid beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast m edia of gene carriers(3). A beta 42 aggregates readily and appears to provide a nidus for the subsequent aggregation of A beta 40 (ref. 4), resulting in the formation of innumerable neuritic plaques. To obtain in vivo information about how PS1 mutations cause AD pathology at such early ages, we characterized the neuropathological phenotype of four PS1-FAD patients from a large Colombian kindred(5) bearing the codon 2 80 Glu to Ala substitution (Glu280Ala) PS1 mutation(2). Using antibodi es specific to the alternative carboxy-termini of A beta, we detected massive deposition of A beta 42, the earliest and predominant form of plaque A beta to occur in AD (ref. 6-8), in many brain regions. Comput er-assisted quantification revealed a significant increase in A beta 4 2 but not A beta 40, burden in the brains from 4 PS1-FAD patients comp ared with those from 12 sporadic AD patients. Severe cerebellar pathol ogy included numerous A beta 42-reactive plaques, many bearing dystrop hic neurites and reactive glia. Our results in brain tissue are consis tent with recent biochemical evidence of increased A beta 42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the beta-amyloid precursor protein at th e C-terminus of A beta to favor deposition of A beta 42.