A Pathogenic Presenilin-1 Deletion Causes Abberrant Aβ42 Production in the Absence of Congophilic Amyloid Plaques (original) (raw)

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 ␤-peptide A␤42. Here we report the identification and pathological function of an unusual FAD-associated PS1 deletion (PS1 ⌬I83/⌬M84). This FAD mutation is associated with spastic paraparesis clinically and causes accumulation of noncongophilic A␤-positive "cotton wool" plaques in brain parenchyma. Cerebral amyloid angiopathy due to A␤ deposition was widespread as were neurofibrillary tangles and neuropil threads, although tau-positive neurites were sparse. Although significant deposition of A␤42 was observed, no neuritic pathology was associated with these unusual lesions. Overexpressing PS1 ⌬I83/⌬M84 in cultured cells results in a significantly elevated level of the highly amyloidogenic 42-amino acid amyloid ␤-peptide A␤42. Moreover, functional analysis in Caenorhabditis elegans reveals reduced activity of PS1 ⌬I83/⌬M84 in Notch signaling. Our data therefore demonstrate that a small deletion of PS proteins can pathologically affect PS function in endoproteolysis of ␤-amyloid precursor protein and in Notch signaling. Therefore, the PS1 ⌬I83/⌬M84 deletion shows a very similar biochemical/functional phenotype like all other FAD-associated PS1 or PS2 point mutations. Since increased A␤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.