Association of a Presenilin 1 S170F Mutation With a Novel Alzheimer Disease Molecular Phenotype

Alessandra Piccini, Gianluigi Zanusso, Roberta Borghi, Cristiana Noviello, Salvatore Monaco, Roberta Russo, Gianluca Damonte, Andrea Armirotti, Matteo Gelati, Renzo Giordano, Pamela Zambenedetti, Claudio Russo (+2 others)
2007 Archives of Neurology  
Objective: To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype. Design: Description of a novel phenotype associated with a presenilin 1 mutation. Setting: The subject was an outpatient who was diagnosed at the local referral center. Patient: A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe ␤-amyloid (A␤) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral
more » ... x and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected. Main Outcome Measures: We analyzed the processing of A␤ precursor protein in vitro as well as the A␤ species in brain tissue. Results: The PSEN1 S170F mutation induced a 3-fold increase of both secreted A␤ 42 and A␤ 40 species and a 60% increase of secreted A␤ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated A␤ species ending at both residues 40 and 42. Conclusion: These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the A␤ aggregates' composition.
doi:10.1001/archneur.64.5.738 pmid:17502474 fatcat:vlhpi5kpufgjhowrwtv5xtazii