Genetic association of an (α2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease
Andrew Liao,Roger Nitsch,S.M. Greenberg,Ulrich Finckh,Deborah Blacker,Marilyn S. Albert,G. W. Rebeck,Teresa Gomez-Isla,Anne E. Clatworthy,G. Binetti,Christoph Hock,T. Mueller-Thomsen,Ulrike Mann,K. Zuchowski,U. Beisiegel,Hannes B. Staehelin,John H. Growdon,Rudolph E. Tanzi,B. T. Hyman +18 more
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The hypothesis that the G/G genotype is over-represented in Alzheimer’s disease in an additional independent data set and the presence of the G allele was associated with an increase in Aβ burden in a small series is tested.Abstract:
alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in association with senile plaques (SP) in Alzheimer's disease (AD). A2M has been implicated biochemically in binding and degradation of the amyloid beta (Abeta) protein which accumulates in SP. We studied the relationship between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genotype from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional independent data set: a group of 359 controls and 566 Alzheimer's disease patients. In the hypothesis testing cohort, the G/G genotype increased from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of the G allele was associated with an increase in Abeta burden in a small series. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. These four proteins have each been genetically linked to Alzheimer's disease, suggesting that they may participate in a common disease pathway.read more
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Inflammation and Alzheimer's disease.
Haruhiko Akiyama,Steven W. Barger,Scott R. Barnum,B Bradt,Jürgen Bauer,Greg M. Cole,Neil R. Cooper,Piet Eikelenboom,Mark R. Emmerling,Bernd L. Fiebich,Caleb E. Finch,Sally A. Frautschy,W. S. T. Griffin,Harald Hampel,Michael Hüll,Gary E. Landreth,Lih-Fen Lue,Robert E. Mrak,Ian R. A. Mackenzie,Patrick L. McGeer,M K O'Banion,Joel S. Pachter,Giulio Maria Pasinetti,C Plata-Salaman,Joseph G. Rogers,Russell E. Rydel,Yueyang Shen,Wolfgang J. Streit,Ronald Strohmeyer,I Tooyoma,F L van Muiswinkel,R. Veerhuis,David G. Walker,Scott D. Webster,Beatrice Hauss–Wegrzyniak,Gary L. Wenk,Tony Wyss-Coray +36 more
TL;DR: By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
Journal ArticleDOI
Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study
Maarit Tanskanen,Terhi Peuralinna,Tuomo Polvikoski,Irma-Leena Notkola,Raimo Sulkava,John Hardy,Andrew B. Singleton,Sari Kiuru-Enari,Anders Paetau,Pentti J. Tienari,Liisa Myllykangas +10 more
TL;DR: In this paper, the prevalence and risk factors for SSA in a Finnish autopsied population aged 85 or over, as part of the population-based Vantaa 85+ Autopsy Study (n = 256), were studied.
Journal ArticleDOI
Causative and susceptibility genes for Alzheimer's disease: a review.
TL;DR: It is concluded that a better understanding of the complex aetiology that underlies AD may be achieved likely through a multidisciplinary approach that combines clinical and neurophysiological characterization of AD subtypes and in vivo functional brain imaging studies with molecular investigations of genetic components.
Journal ArticleDOI
The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review.
TL;DR: New data now directly implicate cathepsins as proteases capable of initiating, as well as executing, cell death programs in certain pathologic states, which support the view that the progressive alterations of lysosomal function observed during aging and Alzheimer's disease contribute importantly to the neurodegenerative process in Alzheimer’s disease.
Journal ArticleDOI
Cholinergic dysfunction in diseases with Lewy bodies.
Pietro Tiraboschi,L. A. Hansen,M. Alford,Marwan N. Sabbagh,B. Schoos,Eliezer Masliah,Leon J. Thal,Jody Corey-Bloom +7 more
TL;DR: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes, and the lack of a relationship between ε4 allele dosage and mid frontal Chat activity suggests that other factors may play a role in its decline in LBV.
References
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The Association Between Quantitative Measures of Dementia and of Senile Change in the Cerebral Grey Matter of Elderly Subjects
TL;DR: The expectation of mental disorder shows a steep increase with advancing chronological age, and beyond 75 years a large part of this increase is accounted for by disorders associated with degenerative changes in the central nervous system for which the authors lack remedies at the present time.
Journal ArticleDOI
Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease.
Teresa Gomez-Isla,Richard D. Hollister,H. L. West,Stina Mui,John H. Growdon,Ronald C. Petersen,Joseph E. Parisi,Bradley T. Hyman +7 more
TL;DR: It is suggested that neuronal loss in association areas such as the superior temporal sulcus contributes directly to cognitive impairment in AD.
Journal ArticleDOI
Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions
TL;DR: Colocalization of ApoE and LRP to SPs implies that these molecules may be involved in metabolism of components of SPs, and it is suggested that SPs and reactive astrocytes were also strongly LRP immunoreactive in Alzheimer's disease.
Journal ArticleDOI
Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor.
Dudley K. Strickland,J.D. Ashcom,Suzanne E. Williams,Wilson H. Burgess,M Migliorini,William Scott Argraves +5 more
TL;DR: The apparent identity of LRP and the alpha 2M receptor suggests that this molecule is a multifunctional receptor with the capacity to bind diverse biological ligands and highlights a possible relationship between two previously unrelated biological processes, lipid metabolism and proteinase regulation.
Journal ArticleDOI
Alpha-2 macroglobulin is genetically associated with Alzheimer disease.
Deborah Blacker,Marsha A. Wilcox,Nan M. Laird,Linda Rodes,Steven M. Horvath,Rodney C.P. Go,Rodney T. Perry,Bracie Watson,Susan Spear Bassett,Melvin G. McInnis,Marilyn S. Albert,Bradley T. Hyman,Rudolph E. Tanzi +12 more
TL;DR: A2M, LRP1 and the genes for two other LRP ligands, APOE and APP (encoding the amyloid ß-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.