[Research Articles] Increased in Vivo Amyloid-{beta}42 Production, Exchange, and Loss in Presenilin Mutation Carriers

Sci Transl Med 12 June 2013:
Vol. 5, Issue 189, p. 189ra77
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3005615 Alzheimer’s Disease Rachel Potter1,*, Bruce W. Patterson2,*, Donald L. Elbert3, Vitaliy Ovod1, Tom Kasten1, Wendy Sigurdson1,4, Kwasi Mawuenyega1, Tyler Blazey4,5, Alison Goate4,6,7, Robert Chott2, Kevin E. Yarasheski2, David M. Holtzman1,4,6, John C. Morris1,4,6, Tammie L. S. Benzinger4,5,8 and Randall J. Bateman1,4,6,†

1Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

2Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

3Department of Biomedical Engineering, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, USA.

4Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.

5Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

6Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.

7Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

8Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. ?†Corresponding author. E-mail: batemanr{at}wustl.edu?* These authors contributed equally to this work.

Alzheimer’s disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-ß (Aß) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aß42 compared to Aß40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers. We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related noncarriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aß isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer Pittsburgh compound B (PIB). CNS Aß42 to Aß40 production rates were 24% higher in mutation carriers compared to noncarriers, and this was independent of fibrillar amyloid deposits quantified by PET PIB imaging. The fractional turnover rate of soluble Aß42 relative to Aß40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aß42 into plaques, leading to reduced recovery of Aß42 in cerebrospinal fluid (CSF). Reversible exchange of Aß42 peptides with preexisting unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aß42 is overproduced in the CNS of humans with PSEN mutations that cause AD, and demonstrate that soluble Aß42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aß42 concentrations in the CSF.

Copyright © 2013, American Association for the Advancement of ScienceCitation: R. Potter, B. W. Patterson, D. L. Elbert, V. Ovod, T. Kasten, W. Sigurdson, K. Mawuenyega, T. Blazey, A. Goate, R. Chott, K. E. Yarasheski, D. M. Holtzman, J. C. Morris, T. L. S. Benzinger, R. J. Bateman, Increased in Vivo Amyloid-ß42 Production, Exchange, and Loss in Presenilin Mutation Carriers. Sci. Transl. Med. 5, 189ra77 (2013).

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UCX, India's sixth commodity exchange goes live, introduces Gold, Silver contracts

In precious metals, it has introudced Gold l kg May, July, September and November 2013 contracts and Gold Nano 100 gm, June, July, August, September, October, November and December contracts. Silver 30 kg contract for delivery in June August , November and Silver Nano contracts for June, July, August, September, October, November and December were introduced at launch of the exchange.

MUMBAI (Bullion Street): The Universal Commodity Exchange, the national level electronic commodity exchange in India,has gone live from Friday 19th April, 2013.

In precious metals, it has introudced Gold l kg May, July, September and November 2013 contracts and Gold Nano 100 gm, June, July, August, September, October, November and December contracts. Silver 30 kg contract for delivery in June August , November and Silver Nano contracts for June, July, August, September, October, November and December were introduced at launch of the exchange.?

Promoted by Commex Technology in joint venture with IDBI Bank, IFFCO, Nabard and REC, the exchange has started trading in 11 contracts across nine commodities - gold, silver, crude oil, chana, RSS4 rubber, mustard, soyabean, refined soya oil and turmeric.

In order to attract volumes, the exchange will charge a fee of Re 1 for every transaction totalling Rs 1 lakh for the first three months. However, it has fixed a four-slab fee structure based on the turnover.As an inaugural offer, trading and clearing member are charged a concession membership fee of Rs 2.5 lakh against Rs 5 lakh, while a trading member have to shell out Rs 1 lakh against regular charge of Rs 1.5 lakh. The exchange will also be available on the commonly used ODIN trading platform.

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View the original article here

UCX, India's sixth commodity exchange goes live, introduces Gold, Silver contracts

In precious metals, it has introudced Gold l kg May, July, September and November 2013 contracts and Gold Nano 100 gm, June, July, August, September, October, November and December contracts. Silver 30 kg contract for delivery in June August , November and Silver Nano contracts for June, July, August, September, October, November and December were introduced at launch of the exchange.

MUMBAI (Bullion Street): The Universal Commodity Exchange, the national level electronic commodity exchange in India,has gone live from Friday 19th April, 2013.

In precious metals, it has introudced Gold l kg May, July, September and November 2013 contracts and Gold Nano 100 gm, June, July, August, September, October, November and December contracts. Silver 30 kg contract for delivery in June August , November and Silver Nano contracts for June, July, August, September, October, November and December were introduced at launch of the exchange.?

Promoted by Commex Technology in joint venture with IDBI Bank, IFFCO, Nabard and REC, the exchange has started trading in 11 contracts across nine commodities - gold, silver, crude oil, chana, RSS4 rubber, mustard, soyabean, refined soya oil and turmeric.

In order to attract volumes, the exchange will charge a fee of Re 1 for every transaction totalling Rs 1 lakh for the first three months. However, it has fixed a four-slab fee structure based on the turnover.As an inaugural offer, trading and clearing member are charged a concession membership fee of Rs 2.5 lakh against Rs 5 lakh, while a trading member have to shell out Rs 1 lakh against regular charge of Rs 1.5 lakh. The exchange will also be available on the commonly used ODIN trading platform.

?

View the original article here

UCX, India's sixth commodity exchange goes live, introduces Gold, Silver contracts

In precious metals, it has introudced Gold l kg May, July, September and November 2013 contracts and Gold Nano 100 gm, June, July, August, September, October, November and December contracts. Silver 30 kg contract for delivery in June August , November and Silver Nano contracts for June, July, August, September, October, November and December were introduced at launch of the exchange.

MUMBAI (Bullion Street): The Universal Commodity Exchange, the national level electronic commodity exchange in India,has gone live from Friday 19th April, 2013.

In precious metals, it has introudced Gold l kg May, July, September and November 2013 contracts and Gold Nano 100 gm, June, July, August, September, October, November and December contracts. Silver 30 kg contract for delivery in June August , November and Silver Nano contracts for June, July, August, September, October, November and December were introduced at launch of the exchange.?

Promoted by Commex Technology in joint venture with IDBI Bank, IFFCO, Nabard and REC, the exchange has started trading in 11 contracts across nine commodities - gold, silver, crude oil, chana, RSS4 rubber, mustard, soyabean, refined soya oil and turmeric.

In order to attract volumes, the exchange will charge a fee of Re 1 for every transaction totalling Rs 1 lakh for the first three months. However, it has fixed a four-slab fee structure based on the turnover.As an inaugural offer, trading and clearing member are charged a concession membership fee of Rs 2.5 lakh against Rs 5 lakh, while a trading member have to shell out Rs 1 lakh against regular charge of Rs 1.5 lakh. The exchange will also be available on the commonly used ODIN trading platform.

?

View the original article here