Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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

J Biol Chem 276(10): 7233-9

Authors/Editors: Steiner H
Revesz T
Neumann M
Romig H
Grim MG
Pesold B
Kretzschmar HA
Hardy J
Holton JL
Baumeister R
Houlden H
Haass C
Publication Date: 2001
Type of Publication: Journal Article

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 β-peptide Aβ42. Here we report the identification and pathological function of an unusual FAD-associated PS1 deletion (PS1 ΔI83/ΔM84). This FAD mutation is associated with spastic paraparesis clinically and causes accumulation of noncongophilic Aβ-positive "cotton wool" plaques in brain parenchyma. Cerebral amyloid angiopathy due to Aβ deposition was widespread as were neurofibrillary tangles and neuropil threads, although tau-positive neurites were sparse. Although significant deposition of Aβ42 was observed, no neuritic pathology was associated with these unusual lesions. Overexpressing PS1 ΔI83/ΔM84 in cultured cells results in a significantly elevated level of the highly amyloidogenic 42-amino acid amyloid β-peptide Aβ42. Moreover, functional analysis in Caenorhabditis elegans reveals reduced activity of PS1 ΔI83/ΔM84 in Notch signaling. Our data therefore demonstrate that a small deletion of PS proteins can pathologically affect PS function in endoproteolysis of β-amyloid precursor protein and in Notch signaling. Therefore, the PS1 ΔI83/ΔM84 deletion shows a very similar biochemical/functional phenotype like all other FAD-associated PS1 or PS2 point mutations. Since increased Aβ42 production is not associated with classical senile plaque formation, these data demonstrate that amyloid plaque formation is not a prerequisite for dementia and neurodegeneration.

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