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J. Biol. Chem., Vol. 280, Issue 44, 36883-36894, November 4, 2005

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Familial Danish Dementia

CO-EXISTENCE OF DANISH AND ALZHEIMER AMYLOID SUBUNITS (ADan AND A) IN THE ABSENCE OF COMPACT PLAQUES^*

Yasushi Tomidokoro, Tammaryn Lashley, Agueda Rostagno, Thomas A. Neubert¶||, Marie Bojsen-Møller**, Hans Braendgaard, Gordon Plant, Janice Holton, Blas Frangione¶¶, Tamas Révész, and Jorge Ghiso¶¶1

From the Departments of Pathology, ^¶¶Psychiatry, and ^¶Pharmacology and the ^||Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, the Department of Neuropathology and Brain Bank, Institute of Neurology, London WC1N3BG, United Kingdom, the Departments of ^**Neuropathology and Neurology, Århus University Hospital, Århus DK8000, Denmark, and The National Hospital for Neurology and Neurosurgery, London WC1N3BG, United Kingdom

Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in the BRI2 gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and -amyloid (A)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with A-(1-42) and A-(4-42) in 1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas A was mainly A-(4-42). In all cases, the presence of A-(X-40) was negligible, a surprising finding in view of the prevalence of A40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and A molecules was demonstrated in vitro by ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.

Received for publication, April 13, 2005 , and in revised form, August 5, 2005.

^* This work was supported in part by National Institutes of Health Grants AG05891, AG08721, S10RR14662, and NS38777, by the Alzheimer Association, and by the Alzheimer's Disease Research program of the American Health Assistance Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Depts. of Pathology and Psychiatry, New York University School of Medicine, 550 First Ave. (TH-432), New York, NY 10016. Tel.: 212-263-7997; Fax: 212-263-6751; E-mail: ghisoj01{at}popmail.med.nyu.edu.

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