The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology

Topic: Amyloid, tau and blood-test diagnosis

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 beta-peptides (A beta) ending at residue 42 (A beta 42) in plasma and skin fibroblast media of gene carriers. 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 bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation.

@article{lemere1996-8837617,
  author  = {Lemere, C. A. and Lopera, F. and Kosik, K. S. and Lendon, C. L. and Ossa, J. and Saido, T. C. and Yamaguchi, H. and Ruiz, A. and others},
  title   = {{The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology}},
  journal = {Nature medicine},
  year    = {1996},
  doi     = {10.1038/nm1096-1146},
  pmid    = {8837617},
  url     = {https://doi.org/10.1038/nm1096-1146}
}

Key findings

• 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 bearing the codon 280 Glu to Ala substitution (Glu280Ala) PS1 mutation.
• Using antibodies 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.
• Computer-assisted quantification revealed a significant increase in A beta 42, but not A beta 40, burden in the brains from 4 PS1-FAD patients compared with those from 12 sporadic AD patients.

Why it matters

In four patients from a Colombian family with a presenilin 1 mutation, the study found increased A beta 42 deposition and severe cerebellar pathology. It describes how this inherited mutation causes early Alzheimer's pathology but does not provide a treatment, cure, or prevention.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/nm1096-1146
• PubMed: 8837617
• Original source →
• Free full text: Institutional Repository University of Antioquia (University of Antioquia) →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease Nature · 1995-06-01 · usefulness score 64/100 · Genetics
• Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1993-10-01 · usefulness score 53/100 · Genetics
• Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation Proceedings of the National Academy of Sciences of the United States of America · 1994-12-01 · usefulness score 48/100 · Risk genes beyond APOE

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• Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1997-07-01 · usefulness score 48/100 · Risk genes beyond APOE

Related studies in Risk genes beyond APOE

• Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer's disease Journal of neurology, neurosurgery, and psychiatry · 1994-04-01 · usefulness score 53/100
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• Purification and cloning of amyloid precursor protein β-secretase from human brain Nature · 1999-12-01 · usefulness score 52/100 · Disease mechanisms
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