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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques.

Familial Alzheimer's disease (FAD) is frequently associated with mutations in the presenilin-1 (PS1) gene. Almost all PS1- associated FAD mutations reported so far are exchanges of single conserved amino acids and cause the increased production of the highly amyloidogenic 42-residue amyloid beta-peptide Abeta42. Here we report the identification and pathological function of an unusual FAD-associated PS1 deletion (PS1 DeltaI83/DeltaM84). This FAD mutation is associated with spastic paraparesis clinically and causes accumulation of noncongophilic Abeta-positive "cotton wool" plaques in brain parenchyma. Cerebral amyloid angiopathy due to Abeta deposition was widespread as were neurofibrillary tangles and neuropil threads, although tau-positive neurites were sparse. Although significant deposition of Abeta42 was observed, no neuritic pathology was associated with these unusual lesions. Overexpressing PS1 DeltaI83/DeltaM84 in cultured cells results in a significantly elevated level of the highly amyloidogenic 42-amino acid amyloid beta-peptide Abeta42. Moreover, functional analysis in Caenorhabditis elegans reveals reduced activity of PS1 DeltaI83/DeltaM84 in Notch signaling. Our data therefore demonstrate that a small deletion of PS proteins can pathologically affect PS function in endoproteolysis of beta-amyloid precursor protein and in Notch signaling. Therefore, the PS1 DeltaI83/DeltaM84 deletion shows a very similar biochemical/functional phenotype like all other FAD- associated PS1 or PS2 point mutations. Since increased Abeta42 production is not associated with classical senile plaque formation, these data demonstrate that amyloid plaque formation is not a prerequisite for dementia and neurodegeneration.[1]

References

  1. A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques. Steiner, H., Revesz, T., Neumann, M., Romig, H., Grim, M.G., Pesold, B., Kretzschmar, H.A., Hardy, J., Holton, J.L., Baumeister, R., Houlden, H., Haass, C. J. Biol. Chem. (2001) [Pubmed]
 
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