Journal ArticleDOI
Protein expression of BACE1, BACE2 and APP in Down syndrome brains.
TLDR
It is concluded that APP overeexpression seems to be absent during the development of DS brain up to 18–19 weeks of gestational age, however, its overexpression in adult DS brain could lead to disturbance of normal function of APP contributing to neurodegeneration.Abstract:
Down syndrome (DS) is the most common human chromosomal abnormality caused by an extra copy of chromosome 21. The phenotype of DS is thought to result from overexpression of a gene or genes located on the triplicated chromosome or chromosome region. Several reports have shown that the neuropathology of DS comprises developmental abnormalities and Alzheimer-like lesions such as senile plaques. A key component of senile plaques is amyloid beta-peptide which is generated from the amyloid precursor protein (APP) by sequential action of beta-secretases (BACE1 and BACE2) and gamma-secretase. While BACE1 maps to chromosome 11, APP and BACE2 are located on chromosome 21. To challenge the gene dosage effect and gain insight into the expressional relation between beta-secretases and APP in DS brain, we evaluated protein expression levels of BACE1, BACE2 and APP in fetal and adult DS brain compared to controls. In fetal brain, protein expression levels of BACE2 and APP were comparable between DS and controls. BACE1 was increased, but did not reach statistical significance. In adult brain, BACE1 and BACE2 were comparable between DS and controls, but APP was significantly increased. We conclude that APP overexpression seems to be absent during the development of DS brain up to 18-19 weeks of gestational age. However, its overexpression in adult DS brain could lead to disturbance of normal function of APP contributing to neurodegeneration. Comparable expression of BACE1 and BACE2 speaks against the hypothesis that increased beta-secretase results in (or even underlies) increased production of amyloidogenic A beta fragments. Furthermore, current data indicate that the DS phenotype cannot be fully explained by simple gene dosage effect.read more
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Journal ArticleDOI
A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome
Frances K. Wiseman,Tamara Al-Janabi,John Hardy,Annette Karmiloff-Smith,Dean Nizetic,Victor L. J. Tybulewicz,Elizabeth M. C. Fisher,Andre Strydom +7 more
TL;DR: Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease, and the presence of three copies of the gene encoding amyloid precursor protein is thought to play a part.
Journal ArticleDOI
Aneuploidy: Cells Losing Their Balance
TL;DR: The history of studies on aneuploidy is reviewed, some of its major characteristics are summarized and speculations as to whether and how aneuPLoidy contributes to tumorigenesis are considered.
Journal ArticleDOI
MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders
TL;DR: The current understanding of the role of miRNAs in the central nervous system is reviewed with emphasis on their impact on the etiopathogenesis of sporadic AD.
Journal ArticleDOI
Aging in Down syndrome and the Development of Alzheimer's disease Neuropathology
TL;DR: It will be critical in the future to develop networked brain banks with standardized collection procedures to fully characterize the regional and temporal pathological events associated with aging in DS.
Journal ArticleDOI
Down’s syndrome, neuroinflammation, and Alzheimer neuropathogenesis
TL;DR: The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review.
References
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Book
The Metabolic and Molecular Bases of Inherited Disease
TL;DR: In this paper, the authors present a list of disorders of MITOCHONDRIAL FUNCTION, including the following: DISORDERS OF MIOCHONDRIC FERTILITY XIX, XVI, XIX.
Journal ArticleDOI
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
Robert Vassar,Brian D. Bennett,Safura Babu-Khan,Steve Kahn,Elizabeth A. Mendiaz,Paul Denis,David B. Teplow,Sandra Ross,Patricia Amarante,Richard Loeloff,Yi Luo,Seth Fisher,Janis Fuller,Steven P. Edenson,Jackson Lile,Mark A. Jarosinski,Anja Leona Biere,Eileen Curran,Teresa L. Burgess,Jean Claude Louis,Frank H. Collins,James J. S. Treanor,Gary Rogers,Martin Citron +23 more
TL;DR: Overexpression of a transmembrane aspartic protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta- secretase positions.
Journal ArticleDOI
Purification and cloning of amyloid precursor protein beta-secretase from human brain.
Sukanto Sinha,John P. Anderson,Robin Barbour,Guriqbal S. Basi,Russell J. Caccavello,David Davis,Minhtam Doan,Harry F. Dovey,Normand Frigon,Jin Hong,Kirsten L. Jacobson-Croak,Nancy Jewett,Pamela S. Keim,J. Knops,Ivan Lieberburg,Michael Power,Hua Tan,Gwen Tatsuno,Jay Tung,Dale Schenk,Peter Seubert,Susanna Suomensaari,Shuwen Wang,Donald A. Walker,Jun Zhao,Lisa McConlogue,Varghese John +26 more
TL;DR: A membrane-bound enzyme activity that cleaves full-length APP at the β-secretase cleavage site is described and found to be the predominant β-cleavage activity in human brain, and it is found that human brain β- secretase is a new membrane- bound aspartic proteinase.
Journal ArticleDOI
Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity.
Riqiang Yan,Michael Jerome Bienkowski,Mary E. Shuck,Huiyi Miao,Monica C. Tory,Adele M. Pauley,John R. Brashler,Nancy C. Stratman,W. Rodney Mathews,Allen E. Buhl,Donald B. Carter,Alfredo G. Tomasselli,Luis A. Parodi,Robert L. Heinrikson,Mark E. Gurney +14 more
TL;DR: Asp2 is a new protein target for drugs that are designed to block the production of amyloid β-peptide peptide and the consequent formation ofAmyloid plaque in Alzheimer's disease.
Journal ArticleDOI
Identification of a novel aspartic protease (Asp 2) as beta-secretase.
Ishrut Hussain,David J. Powell,David R. Howlett,David G. Tew,Thomas D. Meek,Conrad Gerald Chapman,Israel S. Gloger,Kay Elizabeth Murphy,Christopher Southan,Dominic M. Ryan,Trudi S. Smith,David Simmons,Frank S. Walsh,Colin Dingwall,Gary Christie +14 more
TL;DR: Asp 2, a novel transmembrane aspartic protease, has the key activities expected of β-secretase, and mutation of either of the putative catalytic aspartyl residues in Asp 2 abrogates the production of the fragments characteristic of cleavage at the β- secretase site.
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