[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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Increasing efficiency of hydrogen production from green algae

New research results from Uppsala University, Sweden, instill hope of efficient hydrogen production with green algae being possible in the future, despite the prevailing scepticism based on previous research. The study, which is published today in the journal PNAS, changes the view on the ability of green algae.

The world must find a way of producing fuel from renewable energy sources to replace the fossil fuels. Hydrogen is today considered one of the most promising fuels for the future and if hydrogen can be produced directly from sunlight you have a renewable and environmentally friendly energy source.

One biological way of producing hydrogen from solar energy is using photosynthetic microorganisms. Photosynthesis splits water into hydrogen ions (H+) and electrons (e-). These can later be combined into hydrogen gas, (H2) with the use of special enzymes called hydrogenases. This occurs in cyanobacteria and green algae, which have the ability to use energy from the sun through photosynthesis and produce hydrogen through their own metabolism.

That green algae can produce hydrogen under certain conditions has been known and studied for about 15 years, but low efficiency has been a problem, i.e. the amount of energy absorbed by the algae that is transformed into hydrogen. One enzyme that has the ability to use sunlight to split water into electrons, hydrogen ions and oxygen is Photosystem II. Several studies have shown that some of the electrons from the enzyme are used to produce hydrogen gas under special conditions. But some have stated that most of the hydrogen gas gets its energy from other paths in the metabolism of the green algae. This would entail that it is not a matter of actual direct production of hydrogen from sunlight, and that green algae are no more efficient as energy crops than plants.

A group of researchers at Uppsala University, led by Senior Lecturer Fikret Mamedov and Professor Stenbjörn Styring, have now made a discovery that changes the view on hydrogen production from green algae. The researchers studied in detail how Photosystem II works in two different strains of the green algae Chlamydomonas reinhardtii. By measuring exactly how the amount and activity of Photosystem II varies under different conditions, and thereby affects hydrogen production, they found that a considerable amount of the energy absorbed by Photosystem II goes directly into hydrogen production.

"As much as 80 per cent of the electrons that the hydrogen-producing hydrogenases need come from Photosystem II, which is much more than previously believed. This means that most of the hydrogen production is driven directly by solar energy. The discovery gives us hope that it in the future will be possible to control the green algae so that the efficiency becomes significantly higher than it is today", says Professor Stenbjörn Styring.

More information: Increased photosystem II stability promotes H2 production in sulfur-deprived Chlamydomonas reinhardtii , www.pnas.org/cgi/doi/10.1073/pnas.1220645110

Journal reference: Proceedings of the National Academy of Sciences

Provided by Uppsala University

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New materials offer solutions to energy production challenges

New materials will have a central role in many of the energy applications of the future. For instance, inexpensive and environmentally friendly thermoelectric materials will be capable of converting waste heat into electricity in both homes and factories in the future.

Nearly all of the new inorganic materials being developed at the Aalto University School of Chemical Technology involve energy - its production, transfer, or storage - in one way or another. New superconductors, as well as materials used in lithium ion batteries, solid oxide fuel cells, and oxygen storage, among other things, are being developed at the laboratory of Academy Professor Maarit Karppinen.

Other interesting projects are the thermoelectric materials being developed at the laboratory, which are capable of extracting electrical energy from waste heat originating from various sources. In future visions these materials will be producing energy in places such as the walls of homes, solar panels, car exhaust pipes and the heat exchangers of power plants. They can also be used as sources of electricity in mobile devices or in cardiac pacemakers, for instance.

'Thermoelectric materials can be used in both small consumer applications as well as large industrial institutions in the production of electricity from waste heat', Karppinen says.

Common to all of the materials developed in the laboratory is that they are based on oxides, which do not damage the environment. Also, they contain inexpensive and easily-available materials, such as zinc, titanium, and iron, instead of costly precious metals.

Hard work and pure coincidence

Karppinen's laboratory engages in pioneering basic research in which the goal is the development of completely new materials. The application point of view is always in the background, but it is not necessarily the primary consideration.

'We try to find compounds and entire families of materials that nobody else in the world has managed to produce yet', she says.

She says that in addition to persistent research , coincidence has had an important role in the work.

'A new material that has been developed into a superconductor has sometimes proven to be a good thermoelectric material, and vice versa. A new kind of cobalt oxide which was supposed to be a promising thermoelectric material proved to be uniquely suitable for the storage of oxygen.'

This is possible because the materials being researched are typically mixed oxide materials which can be used for a number of different applications. 'The materials that I have studied have remained similar over the years, but the variety of their applications has kept growing', Karppinen says.

She studied oxide superconductors already for her doctoral dissertation, which was completed in 1993. After that, she went to Japan, to the Tokyo Institute of Technology, where she spent a total of ten years. In the last five years of this period she served as an assistant professor.

'We continue to cooperate closely. Japan is one of the main players in the development of oxide materials.'

An open-minded approach produces results

The application of different methods of synthesis is a key part of the practical work of a laboratory.

'To find something completely new, it is necessary to have the courage to experiment with production methods that nobody else has ever tried before', Karppinen explains.

For instance, her laboratory has produced oxide materials under ultra-high pressure - in the same kinds of conditions that turn graphite into diamonds. Another important method is atomic layer deposition, or ALD, in which materials are produced as thin films, one atom at a time.

'Some materials will only become stable when they are made in thin film form', she says.

Half of the approximately 20 researchers in Karppinen's laboratory produce materials in the form of thin films, and the other half produce them as powders. Researchers have also used ALD technology to produce new types of hybrid materials combining organic and inorganic layers of atoms.

However, it will be a long time before the materials will have commercial applications.

'Closest to it are thermoelectric materials. They have a very wide range of potential applications', she observes.

Karppinen's role model is Professor John Goodenough of the University of Texas at Austin. At the age of 90, he is still continuing his long career as one of the most important researchers in his field. In the late 1970s he and his small research group developed a lithium ion battery which was taken into commercial production by Sony in 1991.

Karppinen says that this is typical of the time frame from the discovery of a new functional material to its commercialisation.

'Significant discoveries do not necessarily emerge in big laboratories alone. We also have possibilities for practically anything', she says.

Provided by Aalto University

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