Frangione, Blas

Publication Detail

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Iowa variant of familial Alzheimer's disease: accumulation of posttranslationally modified AbetaD23N in parenchymal and cerebrovascular amyloid deposits.

Yasushi Tomidokoro; Agueda Rostagno; Thomas A Neubert; Yun Lu; G William Rebeck; Blas Frangione; Steven M Greenberg; Jorge Ghiso (Profiled Author: Frangione, Blas)

Department of Pathology and Psychiatry, New York University School of Medicine, New York, NY 10016, USA.
The American journal of pathology 2010;176(4):1841-54.

Mutations within the amyloid-beta (Abeta) sequence, especially those clustered at residues 21-23, which are linked to early onset familial Alzheimer's disease (AD), are primarily associated with cerebral amyloid angiopathy (CAA). The basis for this predominant vascular amyloid burden and the differential clinical phenotypes of cerebral hemorrhage/stroke in some patients and dementia in others remain unknown. The AbetaD23N Iowa mutation is associated with progressive AD-like dementia, often without clinically manifested intracerebral hemorrhage. Neuropathologically, the disease is characterized by predominant preamyloid deposits, severe CAA, and abundant neurofibrillary tangles in the presence of remarkably few mature plaques. Biochemical analyses using a combination of immunoprecipitation, mass spectrometry, amino acid sequence, and Western blot analysis performed after sequential tissue extractions to separately isolate soluble components, preamyloid, and fibrillar amyloid species indicated that the Iowa deposits are complex mixtures of mutated and nonmutated Abeta molecules. These molecules exhibited various degrees of solubility, were highly heterogeneous at both the N- and C-termini, and showed partial aspartate isomerization at positions 1, 7, and 23. This collection of Abeta species-the Iowa brain Abeta peptidome-contained clear imprints of amyloid clearance mechanisms yet highlighted the unique neuropathological features shared by a non-Abeta cerebral amyloidosis, familial Danish dementia, in which neurofibrillary tangles coexist with extensive pre-amyloid deposition in the virtual absence of fibrillar lesions. These data therefore challenge the importance of neuritic plaques as the sole contributors for the development of dementia.

4 Originating Grant

• 1.

  Gandy, Samuel E

  Interdisciplinary Approach to Alzheimer Drug Discovery

  30 September 1991 - 31 August 2010

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 11,063,275

• 2.

  GREENGARD, PAUL

  INTERDISCIPLINARY APPROACH TO ALZHEIMER DRUG DISCOVERY

  30 September 1991 - 31 July 1996

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 2,198,300

• 3.

  Frangione, Blas

  Amyloidosis and Alzheimer's Disease

  1 July 1985 - 30 June 2007

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 4,467,436

• 4.

  FRANGIONE, BLAS

  AMYLOIDOSIS AND ALZHEIMERS DISEASE

  1 July 1985 - 30 June 1997

  NATIONAL INSTITUTE ON AGING

  Total Funding: $ 3,049,140

Scientific Context

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