A pathogenic presenilin-1 deletion causes abberrant Aβ42 production in the absence of congophilic amyloid plaques

Familial Alzheimer's disease (FAD) is frequently associated with mutations in the preseniln-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 A beta 42, Here we report the identification and pathological function of an unusual FAD-associated PS1 deletion (PS1 Delta I83/Delta M84). This FAD mutation is associated with spastic paraparesis clinically and causes accumulation of noncongophilic A beta -positive cotton wool plaques in brain parenchyma, Cerebral amyloid angiopathy due to A beta deposition was widespread as were neurofibrillary tangles and neuropil threads, although tau-positive neurites were sparse. Although significant deposition of A beta 42 was observed, no neuritic pathology was associated with these unusual lesions. Overexpressing PS1 Delta I83/Delta M84 in cultured cells results in a significantly elevated level of the highly amyloidogenic 42-amino acid amyloid beta -peptide A beta 42, Moreover, functional analysis in Caenorhabditis elegans reveals reduced activity of PS1 Delta I83/Delta M84 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 Delta I83/Delta M84 deletion shows a very similar biochemical/functional phenotype like all other FAD-associated PS1 or PS2 point mutations, Since increased A beta 42 production is not associated with classical senile plaque formation, these data demonstrate that amyloid plaque formation is not a prerequisite for dementia and neurodegeneration.