I716F AβPP Mutation Associates with the Deposition of Oligomeric Pyroglutamate Amyloid-β and α-Synucleinopathy with Lewy Bodies

Article type: Research Article

Authors: Sieczkowski, Evelyn^a | Milenkovic, Ivan^b | Venkataramani, Vivek^{c; 1} | Giera, Regina^b | Ströbel, Thomas^b | Höftberger, Romana^b | Liberski, Paweł P.^d | Auff, Eduard^a | Wirths, Oliver^c | Bayer, Thomas A.^c | Kovacs, Gabor G.^{b; *}

Affiliations: [a] Department of Neurology, Medical University of Vienna, Vienna, Austria | [b] Institute of Neurology, Medical University of Vienna, Vienna, Austria | [c] Department of Molecular Psychiatry and Alzheimer, Medical University of Goettingen, Goettingen, Germany | [d] Department of Molecular Pathology and Neuropathology, Medical University of Łódź, Łódź, Poland

Correspondence: [*] Correspondence to: Gabor G. Kovacs, MD PhD, Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, A-1097 Vienna, Austria. Tel.: +43 140400 5504; Fax: +43 140400 55110; E-mail: gabor.kovacs@meduniwien.ac.at.

Note: [1] Current address: Department of Hematology and Oncology, Medical University of Goettingen, Goettingen, Germany.

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.

Keywords: AβPP, α-synuclein, Alzheimer's disease, amyloid-β, dementia with Lewy bodies, N-truncated Aβ, oligomers, pyroglutamate Aβ, tau

DOI: 10.3233/JAD-141524

Journal: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 103-114, 2015