title: A pathogenic presenilin-1 deletion causes abberrant Abeta 42 production in the absence of congophilic amyloid plaques.
abstract: 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.
authors.affiliation: Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Steiner
authors.forename: T
authors.initials: T
authors.lastname: Revesz
authors.forename: M
authors.initials: M
authors.lastname: Neumann
authors.forename: H
authors.initials: H
authors.lastname: Romig
authors.forename: M G
authors.initials: MG
authors.lastname: Grim
authors.forename: B
authors.initials: B
authors.lastname: Pesold
authors.forename: H A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.forename: J L
authors.initials: JL
authors.lastname: Holton
authors.forename: R
authors.initials: R
authors.lastname: Baumeister
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.forename: C
authors.initials: C
authors.lastname: Haass
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000235:genetics*; D010641:Phenotype; D058225:Plaque, Amyloid / Q000737:chemistry*; D017354:Point Mutation; D011233:Precipitin Tests; D053764:Presenilin-1; D051880:Receptors, Notch; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D051880:Receptors, Notch; C075222:amyloid beta-protein (1-42); D005182:Flavin-Adenine Dinucleotide