Search Results - (Author, Cooperation:D. J. Selkoe)

2016-04-02

American Association for the Advancement of Science (AAAS)

0036-8075

1095-9203

Biology

Chemistry and Pharmacology

Computer Science

Medicine

Natural Sciences in General

Physics

2012-09-22

American Association for the Advancement of Science (AAAS)

0036-8075

1095-9203

Biology

Chemistry and Pharmacology

Computer Science

Medicine

Natural Sciences in General

Physics

Alzheimer Disease/diagnosis/etiology/*prevention & control/therapy ; Amyloid beta-Peptides/cerebrospinal fluid/genetics/metabolism ; Animals ; Apolipoproteins E/genetics ; Biomarkers/analysis/cerebrospinal fluid ; Clinical Trials as Topic ; Disease Progression ; Genetic Predisposition to Disease ; Humans ; Life Style ; Mutation ; Peptide Fragments/cerebrospinal fluid ; Secondary Prevention

2011-08-16

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Animals ; Blotting, Western ; COS Cells ; Cell Line, Tumor ; Cercopithecus aethiops ; Erythrocytes/chemistry ; Escherichia coli/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Lipid Metabolism ; Mice ; Protein Folding ; Recombinant Proteins/chemistry/metabolism ; Time Factors ; alpha-Synuclein/*chemistry/genetics/*metabolism

1749-6632

Blackwell Publishing Journal Backfiles 1879-2005

Natural Sciences in General

Electronic Resource

1749-6632

Blackwell Publishing Journal Backfiles 1879-2005

Natural Sciences in General

Electronic Resource

1749-6632

Blackwell Publishing Journal Backfiles 1879-2005

Natural Sciences in General

The amyloid β-protein (Aβ) is a proteolytic fragment of the β-amyloid precursor protein (βAPP). We previously reported the constitutive secretion of Aβ peptides from a variety of cells expressing βAPP under normal culture conditions. These endogenously produced Aβpeptides have heterogeneous N-and C-termini that vary as a function of βAPP missense mutations. Treatment of Aβ-secreting cells with agents that alter intravesicular pH showed that an acidic compartment is required for proper Aβ generation. One such compartment appears to be the endosome. Immunolabeling of cell-surface βAPP in living neurons and non-neuronal cells directly demonstrated the endocytosis of the protein and its rapid recycling (within 5–10 minutes) to the cell surface, as well as the trafficking of some βAPP to lysosomes. Expression of βAPP with various deletions of the cytoplasmic domain, including the NPTY motif, leads to decreased internalization and an associated decrease in the production of Aβ peptides that begin at the usual asp1 start site. These and other data suggest that Aβ production begins with cleavage of βAPP by a still unknown protease(s) (β-secretase[s] at the met-asp bond preceding the Aβ N-terminus and that this occurs in part in early endosomes. To characterize the substrate requirements of β-secretase, βAPP was mutagenized by placing stop codons within or at the end of the transmembrane domain or substituting other amino acids for the wild-type met and asp at the P1 and P1' positions. These experiments showed that proper β-secretase cleavage requires the precursor to be membrane-anchored and is highly sequence specific; most substitutions at met or asp substantially decrease Aβ production. Analogous mutagenesis experiments around the Aβ C-terminus revealed that the unknown protease(s) cleaving here (“γ-secretase[s]”) does not show such specificity. Cells secreting Aβ may also be useful for examining the critical issue of the aggregation of Aβ into its neurotoxic polymeric form under physiological conditions. In this regard, we have found that AβAPP-expressing CHO cells show aggregation of 〈inlineGraphic alt="geqslant R: gt-or-equal, slanted" extraInfo="nonStandardEntity" href="urn:x-wiley:00778923:NYAS57:ges" location="ges.gif"/〉 10-20% of their secreted Aβ peptides into SDS-stable dimers, trimers and sometimes tetramers under normal culture conditions. The identity of these small multimers was confirmed by extensive immunochemical characterization and radiosequencing. They are present at  100-500 pM levels in conditioned medium of CHO transfectants. Using this endogenous Aβ aggregating system, we have begun to examine variables that influence aggregation and compounds which may retard it. In conclusion, studies of the regulation of Aβ production and aggregation in cell culture can provide information under physiological conditions that can complement analyses of these processes in vivo.

Electronic Resource

1749-6632

Blackwell Publishing Journal Backfiles 1879-2005

Natural Sciences in General

Electronic Resource

1432-0533

Neurofibrillary tangles ; Paired helical filaments ; Amyloid-like ; Neurofilaments ; Alzheimer's disease ; Immunohistochemistry

Springer Online Journal Archives 1860-2000

Medicine

Summary The immunohistological properties of Alzheimer's neurofibrillary tangles (NFT) were studied by immunofluorescence with neurofilament (NF) antisera and with antiserum raised to paired helical filaments (PHF) in NFT preparations, brain smears, and cryostat sections. NFT decorated by NF antisera were Congo red-negative. Conversely, PHF antisera stained Congo red-positive NFT but failed to decorate NF-positive NFT. It is concluded that NF do not cross react with typical NFT, i.e., NFT displaying amyloid-like birefringence, under the conditions reported in this study.

Electronic Resource

1432-0533

Locus ceruleus ; Pick bodies ; Lewy bodies ; Immunocytochemistry ; Electron microscopy

Springer Online Journal Archives 1860-2000

Medicine

Summary In classical Pick's disease with typical Pick bodies, inclusions resembling those present in the cerebral cortex are frequently found in the locus ceruleus. In three such cases Pick bodies were studied by light and electron microscopy and compared with Lewy bodies, inclusions more commonly found in this location. In contrast to the situation in the cerebral cortex, nerve cells with multiple Pick bodies were often found in the locus ceruleus, but in other respects definite light and electron microscopic differences between Pick bodies and Lewy bodies were present. Pick bodies were slightly basophilic and never had a central core or a peripheral halo. They were intensely argyrophilic. Differences in immunocytochemical reactions were especially marked with antibodies to tau and to paired helical filaments. Pick bodies displayed an intense reaction with these two antibodies, contrasting with that of Lewy bodies, which either lacked reactivity or reacted in a peripheral band. By electron microscopy the Pick bodies were composed of random filaments with smooth contour, whereas typical Lewy bodies had fuzzy deposits on filaments that radiated from a central core. Pick bodies in the locus ceruleus therefore maintained their immunocytochemical and electron microscopic characteristics and did not take on the character of Lewy bodies. Such differences point to a different pathogenesis and perhaps etiology of these two types of inclusions and attest to the marked difference clinically and pathologically between Pick's and Parkinson's diseases.

Electronic Resource

1435-1463

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource