The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology

Cynthia A. Lemere, Francisco Lopera, Kenneth S. Kosik, Corrine L. Lendon, Jorge Ossa, Takaomi C. Saido, Haruyasu Yamaguchi, Andres Ruiz, Alonso Martinez, Lucia Madrigal, Liliana Hincapie, Juan Carlos Arango L., Douglas C. Anthony, Edward H. Koo, Alison M. Goate, Dennis J. Selkoe, Juan Carlos Arango V.

Research output: Contribution to journalArticlepeer-review

452 Scopus citations


Missense mutations in the presenilin 1 (PS1) gene cause the most common form of dominant early-onset familial Alzheimer's disease (FAD) and are associated with increased levels of amyloid β-peptides (Aβ) ending at residue 42 (Aβ42) in plasma and skin fibroblast media of gene carriers. Aβ42 aggregates readily and appears to provide a nidus for the subsequent aggregation of Aβ40 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 phonotype of four PS1-FAD patients from a large Colombian kindred bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation. Using antibodies specific to the alternative carboxy-termini of Aβ, we detected massive deposition of Aβ42, the earliest and predominant form of plaque Aβ to occur in AD in many brain regions. Computer-assisted quantification revealed a significant increase in Aβ42, but not Aβ40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients. Severe cerebellar pathology included numerous Aβ42-reactive plaques, many bearing dystrophic neurites and reactive glia. Our results in brain tissue are consistent with recent biochemical evidence of increased Aβ42 levels in PS1-FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the β-amyloid precursor protein at the C-terminus of Aβ to favor deposition of Aβ42.

Original languageEnglish
Pages (from-to)1146-1150
Number of pages5
JournalNature Medicine
Issue number10
StatePublished - Oct 1996
Externally publishedYes


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