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Holtzman D.M.,University of Washington | Mandelkow E.,Max Planck Unit for Structural Molecular Biology | Mandelkow E.,German Center for Neurodegenerative Diseases | Selkoe D.J.,Harvard University
Cold Spring Harbor Perspectives in Biology

Remarkable advances in unraveling the biological underpinnings of Alzheimer disease (AD) have occurred during the last 25 years. Despite this,we have made only the smallest of dents in the development of truly disease-modifying treatments. What will change over the next 10 years? While the answer is not clear, we make several predictions on the state of the field in 2020, based on the rich knowledge described in the other contributions in this collection. As such, our predictions represent some of the principal unresolved questions that we believe deserve special investigative attention in the coming decade. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Source

Swaminathan R.,Indian Institute of Technology Guwahati | Ravi V.K.,Indian Institute of Technology Guwahati | Kumar S.,Max Planck Unit for Structural Molecular Biology | Kumar M.V.S.,Indian Institute of Science | Chandra N.,Indian Institute of Technology Guwahati
Advances in Protein Chemistry and Structural Biology

Ever since lysozyme was discovered by Fleming in 1922, this protein has emerged as a model for investigations on protein structure and function. Over the years, several high-resolution structures have yielded a wealth of structural data on this protein. Extensive studies on folding of lysozyme have shown how different regions of this protein dynamically interact with one another. Data is also available from numerous biotechnological studies wherein lysozyme has been employed as a model protein for recovering active recombinant protein from inclusion bodies using small molecules like l-arginine. A variety of conditions have been developed in vitro to induce fibrillation in hen lysozyme. They include (a) acidic pH at elevated temperature, (b) concentrated solutions of ethanol, (c) moderate concentrations of guanidinium hydrochloride at moderate temperature, and (d) alkaline pH at room temperature. This review aims to bring together similarities and differences in aggregation mechanisms, morphology of aggregates, and related issues that arise using the different conditions mentioned above to improve our understanding. The alkaline pH condition (pH 12.2), discovered and studied extensively in our lab, shall receive special attention. More than a decade ago, it was revealed that mutations in human lysozyme can cause accumulation of large quantities of amyloid in liver, kidney, and other regions of gastrointestinal tract. Understanding the mechanism of lysozyme aggregation will probably have therapeutic implications for the treatment of systemic nonneuropathic amyloidosis. Numerous studies have begun to focus attention on inhibition of lysozyme aggregation using antibody or small molecules. The enzymatic activity of lysozyme presents a convenient handle to quantify the native population of lysozyme in a sample where aggregation has been inhibited. The rich information available on lysozyme coupled with the multiple conditions that have been successful in inducing/inhibiting its aggregation in vitro makes lysozyme an ideal model protein to investigate amyloidogenesis. © 2011 Elsevier Inc. All rights reserved. Source

Korhonen P.,University of Eastern Finland | van Groen T.,University of Alabama at Birmingham | Thornell A.,University of Eastern Finland | Kyrylenko S.,University of Eastern Finland | And 7 more authors.
Neurobiology of Aging

We have established a novel transgenic rat line carrying human microtubule-associated protein Tau-40 with mutation P301L. hTau-40/P301L transgenic male and female rats were followed up to 2 years of age. The hTau-40/P301L rats expressed human tau mRNA and protein in the limbic cortex and associated white matter, hippocampus and spinal cord. With increasing age, the staining density for phosphorylated tau increased in all these areas. Neither silver stains nor Fluoro-Jade staining indicated the presence of dying neurons, or axonal degeneration, and there was no evidence of increased gliosis or inflammation. However, some neurons did display dendritic abnormalities, and immunoblots revealed the presence of sarcosyl insoluble tau. A large test battery revealed no behavioral abnormalities in these rats, except a mild hyperactivity in the elevated plus maze. In conclusion, this transgenic tau rat may be a useful model for 'pretangle' pathology, although in this study conditions were not sufficient to induce significant neuronal loss or behavioral deficits. © 2010 Elsevier Inc. Source

Sydow A.,Max Planck Unit for Structural Molecular Biology | Mandelkow E.-M.,Max Planck Unit for Structural Molecular Biology
Neurodegenerative Diseases

Background: Aggregates of the tau protein are a hallmark of Alzheimer's and several other neurodegenerative diseases. Various transgenic mouse models have been generated to study the aggregation process. Since wild-type tau is highly soluble and does not aggregate readily, most models make use of tau mutations that occur in human frontotemporal dementias and are more prone to aggregate. These mouse models show neurofibrillary tangles similar to those of Alzheimer's disease. However, since the mice contain both endogenous wild-type mouse tau and exogenous human mutant tau, the relative contribution of these components to the aggregates has been a matter of debate. Objective:Using a new set of regulatable transgenic mouse models, we sought to determine whether mouse tau coaggregates with human tau when it is switched on. Furthermore, we asked what type of tau remains in the aggregates after switching off the expression of exogenous tau. Methods: We generated doxycycline-inducible transgenic mice expressing either full-length human tau or the tau repeat domain (tau RD). In addition, both types of human tau derivatives were expressed in a 'proaggregant' form (with the frontotemporal dementia with parkinsonism linked to chromosome 17 mutation ΔK280), or in an 'antiaggregant' form (with additional proline mutations to block β-structure and aggregation). Results:The proaggregant tauRD mice develop tangles rapidly after induction, the antiaggregant mice do not. Analysis by biochemistry and immunohistology reveals that the tangles contain both exogenous and endogenous mouse tau. After switching off the proaggregant tauRD, tangles persist for extended periods. However, they are composed entirely of mouse tau. Conclusions:Mouse tau and exogenous human tau can coaggregate in transgenic models of tauopathy. The aggregates are in dynamic equilibrium with their subunits, so that exogenous tau disappears when its expression is switched off. Once the seeds of aggregation are generated by the foreign tau species, they propagate in a 'prion-like' fashion within the cell even after the foreign tau has disappeared. Copyright © 2010 S. Karger AG, Basel. Source

Schirmer R.H.,University of Heidelberg | Adler H.,University of Heidelberg | Pickhardt M.,Max Planck Unit for Structural Molecular Biology | Pickhardt M.,German Center for Neurodegenerative Diseases | And 2 more authors.
Neurobiology of Aging

Methylene blue (MB), the first synthetic drug, has a 120-year-long history of diverse applications, both in medical treatments and as a staining reagent. In recent years there was a surge of interest in MB as an antimalarial agent and as a potential treatment of neurodegenerative disorders such as Alzheimer's disease (AD), possibly through its inhibition of the aggregation of tau protein. Here we review the history and medical applications of MB, with emphasis on recent developments. © 2011 Elsevier Inc. Source

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