Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy

Grabowski, Thomas J.; Cho, Hyun Soon; Vonsattel, Jean Paul; Rebeck, G. William; Greenberg, Steven M.

doi:10.1002/ana.1009

Cited by 492 publications

(509 citation statements)

References 45 publications

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“…We found the amyloid ␤A4 protein and cell-surface receptor, mutations of which are related to Alzheimer (22), dementia, and severe cerebral amyloid angiopathy (23). Other disease-related proteins found comprise defender against cell death 1 protein and programmed cell death 6 interacting protein that are involved in apoptosis.…”

Section: Identification Of Channel Proteins and Other Brain Diseaserementioning

confidence: 90%

Proteomic Mapping of Brain Plasma Membrane Proteins

Nielsen¹,

Olsen

Podtelejnikov³

et al. 2005

Molecular & Cellular Proteomics

158

204

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Proteomics is potentially a powerful technology for elucidating brain function and neurodegenerative diseases. So far, the brain proteome has generally been analyzed by two-dimensional gel electrophoresis, which usually leads to the complete absence of membrane proteins. We describe a proteomic approach for profiling of plasma membrane proteins from mouse brain. The procedure consists of a novel method for extraction and fractionation of membranes, on-membrane digestion, diagonal separation of peptides, and high-sensitivity analysis by advanced MS. Breaking with the classical plasma membrane fractionation approach, membranes are isolated without cell compartment isolation, by stepwise depletion of nonmembrane molecules from entire tissue homogenate by high-salt, carbonate, and urea washes followed by treatment of the membranes with sublytic concentrations of digitonin. Plasma membrane is further enriched by of density gradient fractionation and protein digested on-membrane by endoproteinase Lys-C. Released peptides are separated, fractions digested by trypsin, and analyzed by LC-MS/MS. In single experiments, the developed technology enabled identification of 862 proteins from 150 mg of mouse brain cortex. Further development and miniaturization allowed analysis of 15 mg of hippocampus, revealing 1,685 proteins. More that 60% of the identified proteins are membrane proteins, including several classes of ion channels and neurotransmitter receptors. Our work now allows in-depth study of brain membrane proteomes, such as of mouse models of neurological disease.

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Section: Identification Of Channel Proteins and Other Brain Diseaserementioning

confidence: 90%

Proteomic Mapping of Brain Plasma Membrane Proteins

Nielsen¹,

Olsen

Podtelejnikov³

et al. 2005

Molecular & Cellular Proteomics

158

204

View full text Add to dashboard Cite

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“…This viewpoint is supported by the two hereditary disorders FBD and FDD (collectively known as chromosome 13 dementias) and by the Iowa variant of familial AD associated with the deposition of the mutant A␤D23N (63). Despite the structural differences among ABri, ADan, and A␤, the absence or limited number of compact plaques and extensive neurofibrillar degeneration with tangles identical to those found in Alzheimer brains are main features of these disorders.…”

Section: Discussionmentioning

confidence: 99%

Familial Danish Dementia

Tomidokoro

Lashley²,

Rostagno

et al. 2005

Journal of Biological Chemistry

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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 ϳ1:1 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 A␤40 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. Theabsenceofcompactplaquesinthepresenceofextensiveneurofibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.

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“…This smaller region may also be important in initiating aggregation, as suggested by aggregation studies of myriad mutation forms. For example, Flemish (A21G) (61), Arctic (E22G) (62), Dutch (E22Q) (61,63), Iowa (D23N) (64), and others (65) exhibit different aggregation behavior compared with the wild-type Aβ 42 , supporting that the middle region of Aβ is important in the aggregation process. The C terminus (residues 36-42) aggregates second, confirming that it plays a smaller but still important role in aggregation (49).…”

Section: Application Of Finke-watzky Modeling and Statistical Evaluatmentioning

confidence: 99%

Pulsed hydrogen–deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation

Zhang

Rempel

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

113

179

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Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aβ 42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ 42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ 42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu 2+ ions. This MS approach has sufficient structural resolution to allow interrogation of Aβ aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates.soluble Aβ oligomers | amyloid beta peptide | copper | electrospray ionization | Finke-Watsky mode P rotein aggregation is one of the immediate causes of Alzheimer's, Parkinson, and Huntington diseases, motivating biophysical studies of the responsible proteins. More than 20 small proteins undergo amyloidosis in humans. In Alzheimer's disease (AD), the aggregation of the 40-or 42-aa-long amyloid beta (Aβ) peptide, generally called Aβ 40 or Aβ 42 , respectively, is proposed to be involved in the onset of the disease (1, 2). Aβ 42 is more amyloidogenic and more neurotoxic than Aβ 40 . Although the amyloid-cascade hypothesis suggests that the Aβ-containing amyloid plaques are responsible for neurodegeneration (3-7), other studies suggest that soluble aggregates of Aβ 42 are more neurotoxic than the amyloid plaques (8-13).The amyloid plaques in AD-affected brains contain high levels of copper, zinc, and iron (14-20). Among these, Cu has drawn the most attention because the Aβ precursor protein is likely a Cuchaperone protein (21). Several studies of Cu 2+ -Aβ 40 interactions show that Cu 2+ can promote Aβ 40 aggregation (14,18,19).The structure of Aβ 42 and its aggregates, although studied extensively, remains of high interest. Studies of amyloid fibrils invoke X-ray crystallography (22-24), EM (19,25,26), and thioflavin T fluorescence (19, 27), revealing the polypeptide's global behavior, whereas NMR studies provide residue-level information for the fibrils (28-30). Nevertheless, we know little about soluble Aβ aggregates owing to their intrinsically high heterogeneity.MS should offer an opportunity for investigating soluble aggregates of Aβ 42 . Thus far, there are no MS-based, timedependent studies of the formation of soluble aggregates. Moreover, there are no ot...

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Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy

Cited by 492 publications

References 45 publications

Proteomic Mapping of Brain Plasma Membrane Proteins

Proteomic Mapping of Brain Plasma Membrane Proteins

Familial Danish Dementia

Pulsed hydrogen–deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation

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