title: I716F AβPP mutation associates with the deposition of oligomeric pyroglutamate amyloid-β and α-synucleinopathy with Lewy bodies.
abstract: Autosomal dominant familial Alzheimer's disease (AD) is associated with mutations in the AβPP, PSEN1, and PSEN2 genes. The clinical phenotype associated with AβPP mutations is mainly characterized by dementia or by strokes related to cerebral amyloid angiopathy (CAA). We present a comprehensive clinical, neuropathological, genetic, and biochemical study on a patient affected by familial AD associated with the I716F mutation in the AβPP gene. The clinical phenotype was characterized by early age of onset of 47 years, and rapidly progressive cerebellar ataxia, myoclonic jerks, rigidity, and dementia reminiscent of Creutzfeldt-Jakob disease (CJD), followed by a prolonged persistent vegetative state. Neuropathological evaluation of the proband revealed AD-related pathology but also α-synucleinopathy compatible with dementia with Lewy bodies neocortical stage or Parkinson's disease corresponding to Braak stage 6. Tau-pathology in the form of neurofibrillary degeneration corresponded to stage VI according to the Braak classification. The severe Aβ pathology included CAA, numerous plaques, and deposition of N-truncated pyroglutamate-modified Aβ peptides. Remarkably, pyroglutamate Aβ oligomers were also present intracellularly in Purkinje cells corresponding to the ataxic phenotype. The detection of a CJD-like phenotype expands the spectrum of clinical presentations associated with familial AD. Our study supports the concept that the neuropathology of familial AD expands beyond the classical AD-related pathology as defined by plaques and tangles. Finally, we provide evidence for the first time that oligomeric pyroglutamate Aβ is present in a specific pattern correlating with the clinical symptoms of a patient with AβPP I716F mutation.
authors.affiliation: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Sieczkowski
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ivan
authors.initials: I
authors.lastname: Milenkovic
authors.affiliation: Department of Molecular Psychiatry and Alzheimer, Medical University of Goettingen, Goettingen, Germany.
authors.forename: Vivek
authors.initials: V
authors.lastname: Venkataramani
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Giera
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ströbel
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.affiliation: Department of Molecular Pathology and Neuropathology, Medical University of Łódź, Łódź, Poland.
authors.forename: Paweł P
authors.initials: PP
authors.lastname: Liberski
authors.affiliation: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Eduard
authors.initials: E
authors.lastname: Auff
authors.affiliation: Department of Molecular Psychiatry and Alzheimer, Medical University of Goettingen, Goettingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wirths
authors.affiliation: Department of Molecular Psychiatry and Alzheimer, Medical University of Goettingen, Goettingen, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005820:Genetic Testing; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009483:Neuropsychological Tests; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D051844:alpha-Synuclein; D016875:tau Proteins
keywords: Alzheimer's disease; AβPP; N-truncated Aβ; amyloid-β; dementia with Lewy bodies; oligomers; pyroglutamate Aβ; tau; α-synuclein