Clinical, Neuropathologic, and Biochemical Profile of the Amyloid Precursor Protein 1716F Mutation
Por:
Guardia-Laguarta, C, Pera, M, Clarimon, J, Molinuevo, JL, Sanchez-Valle, R, Llado, A, Coma, M, Gomez-Isla, T, Blesa, R, Ferrer, I, Lleo, A
Publicada:
1 ene 2010
Resumen:
We report the clinical, pathologic, and biochemical characteristics of the recently described amyloid precursor protein (APP) 1716F mutation. We present the clinical findings of individuals carrying the APP 1716F mutation and the neuropathologic examination of the proband. The mutation was found in a patient with Alzheimer disease with onset at the age of 31 years and death at age 36 years and who had a positive family history of early-onset Alzheimer disease. Neuropathologic examination showed abundant diffuse amyloid plaques mainly composed of amyloid-beta(42) and widespread neurofibrillary pathology. Lewy bodies were found in the amygdala. Chinese hamster ovary cells transfected with this mutation showed a marked increase in the amyloid-beta(42/40) ratio and APP C-terminal fragments and a decrease in APP intracellular domain production, suggesting reduced APP proteolysis by gamma-secretase. Taken together, these findings indicate that the APP 1716F mutation is associated with the youngest age of onset for this locus and strengthen the inverse association between amyloid-beta(42/40) ratio and age of onset. The mutation leads to a protein that is poorly processed by gamma-secretase. This loss of function may be an additional mechanism by which some mutations around the gamma-secretase cleavage site lead to familial Alzeheimer disease.
Filiaciones:
Guardia-Laguarta, C:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Pera, M:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08025, Spain
Clarimon, J:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Molinuevo, JL:
Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Dept Neurol, Barcelona, Spain
Sanchez-Valle, R:
Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Dept Neurol, Barcelona, Spain
Coma, M:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Gomez-Isla, T:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Blesa, R:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Ferrer, I:
Univ Barcelona, Fac Med, IDIBELL Hosp Univ Bellvitge, Serv Anat Patol,Inst Neuropatol, Barcelona 7, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Lleo, A:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, Dept Neurol, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Barcelona, Spain
Hosp Clin Barcelona, Alzheimers Dis & Other Cognit Disorders Unit, Dept Neurol, Barcelona, Spain
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