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Association of a Presenilin 1 S170F Mutation With a Novel Alzheimer Disease Molecular Phenotype
Alessandra Piccini, PhD;
Gianluigi Zanusso, MD, PhD;
Roberta Borghi, PhD;
Cristiana Noviello, PhD;
Salvatore Monaco, MD;
Roberta Russo, PhD;
Gianluca Damonte, PhD;
Andrea Armirotti, PhD;
Matteo Gelati, PhD;
Renzo Giordano, MD;
Pamela Zambenedetti, MD;
Claudio Russo, PhD;
Bernardino Ghetti, MD;
Massimo Tabaton, MD
Arch Neurol. 2007;64(5):738-745.
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 β-amyloid (Aβ) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex 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 Aβ precursor protein in vitro as well as the Aβ species in brain tissue.
Results The PSEN1 S170F mutation induced a 3-fold increase of both secreted Aβ42 and Aβ40 species and a 60% increase of secreted Aβ precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N–terminally truncated Aβ 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 Aβ aggregates' composition.
Author Affiliations: Departments of Neurosciences, Ophthalmology, and Genetics (Drs Piccini, Borghi, R. Russo, and Tabaton), Experimental Medicine, Center of Excellence for Biomedical Research (Drs Damonte and Armirotti), and Oncology, Biology, and Genetics (Dr C. Russo), University of Genoa, Genoa, Department of Neurological and Visual Sciences, University of Verona, Verona (Drs Zanusso, Monaco, and Gelati), CEINGE Advanced Biotechnologies, Naples (Dr Noviello), and Division of Anatomic Pathology, Dolo General Hospital, Venice (Drs Giordano and Zambenedetti), Italy; and Indiana Alzheimer Disease Center, Indiana University, Indianapolis (Dr Ghetti).
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