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P3–193: Genotype–phenotype relationship is lacking in families with PS1–Met146Leu founder mutation

2006; Wiley; Volume: 2; Issue: 3S_Part_14 Linguagem: Inglês

10.1016/j.jalz.2006.05.1461

1552-5279

Amalia C. Bruni, Beatrice Terni, Livia Bernardi, Carmine Tomaino, Raffaele Maletta, Nicoletta Smirne, Cinzia Calignano, Annamaria Paonessa, Attilio Leotta, Santo Lio, Gianfranco Puccio, Rosanna Colao, Francesca Frangipane, Sabrina A.M. Curcio, Maria Mirabelli, Hamid El. Hachimi, J F Foncin, Maria Grazia Spillantini,

Alzheimer's disease research and treatments

PS1–Met146Leu segregates in distinct families scattered worldwide, belonging to two large kindreds reconstructed up to the XVIIth and whose common origin was found in southern Italy. Both families show classical AD neuropathology. A PS1–Met146Leu AD family with Pick bodies has been described in Australia, one of the ancestors signalled as an “Italian woman”. Genealogical enquiry evidenced that she was born in Cairo (Egypt) in 1895 of Italian parents descending from the common ancestor of the PS1–Met146Leu family. To study tau pathology of PS1–Met146Leu Italian branch. Paraffin–embedded brain sections belonging to two PS1–Met146Leu Italian patients were immunohistochemically stained with anti–phospho tau antibody AT8, anti–3R (RD3) and anti–4Repeats tau (RD4) antibodies. Immunoblot of sarcosyl–insoluble tau was also performed. Immunohistochemical staining of the hippocampus and cortex revealed widespread tau pathology. Abundant neuritic plaques, neurofibrillary tangles and neuropil threads were observed in both areas by antibodies AT8 and RD3 while fewer deposits were stained by antibody RD4. Occasional Pick body–like inclusions were observed in the hippocampus; these structures were more numerous in the cortical area although their number was limited, compared to the other type of tau aggregates. Double staining with AT8 and RD4 showed that, differently from Pick bodies found in sporadic Pick disease, the observed inclusions could contain tau with 4 repeats. Immunoblot of sarcosyl–insoluble tau extracted from parietal, frontal and temporal cortex showed the 4 bands of 60, 64, 68 and 72 kDa characteristic of Alzheimer's disease cases. Although by immunohistochemistry RD3 antibody recognized more tau deposits than RD4, dephosphorylation of sarcosyl–insoluble tau with alkaline phosphatase showed the presence of all 6 tau isoforms in all investigated cortical areas. The Italian branch shows only occasional Pick body–like inclusions. Moreover, the presence of all tau isoforms account for a clear AD pathology.In view of the fact that Pick bodies have been indicated as an important feature in the Australian branch of the same family we can conclude that PSI–Met146Leu mutation can present variable neuropathological features suggesting that during centuries environmental and genetic factors can contribute to modify the phenotype.