Accumulation Of Abeta Peptides Research Articles

A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) pep-tides, products of the proteolytic cleavage of the amy-loid precursor protein APP. Increasing evidence sug-gests that Abeta peptides also accumulate intracellular-ly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 - e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facili-tate the aggregation of Abeta peptides into small oli-gomers and promote their translocation to mitochon-dria. Deletion or downregulation of this chaperone pro-tected from Abeta-mediated toxicity in yeast and Dro-sophila AD models, respectively. Most importantly, the identified chaperone is found to be dysregulated in post-mortem human samples of AD patients. Here, we aim to outline our key findings, highlighting pathological functions of a heat shock protein (Hsp) family member, which are generally considered protective rather than toxic during neurodegeneration. Our results thus chal-lenge the concept of developing generalized chaperone activation-based therapies and call for carefully consid-ering also maladaptive functions of specific heat shock proteins.

Alzheimer's disease and CADASIL are heritable, adult-onset dementias that both involve damaged small blood vessels.

This essay explores an alternative pathway to Alzheimer's dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.

Regulatory T cells delay disease progression in a murine model of Alzheimer�s disease

Regulatory T cells delay disease progression in a murine model of Alzheimer�s disease

Neuroprotection and Neuroregeneration in Alzheimer's Disease

Neurodegeneration in Alzheimer's disease (AD) is thought to be initiated by a cascade of neurotoxic events that include oxidative stress, brain iron dysregulation, glutamate excitotoxicity, nitric oxide, inflammatory process, neurotoxic processing resulting from misfolding, and aggregation of Abeta peptide, as a possible consequence of the demise of ubiquitin-proteasome system (UPS) which is demonstrated neurochemically and by transcriptomics and proteomic profiling. AD is benefitted from the symptomatic effects of cholinesterase inhibitors and glutamate antagonist (memantine), which act on a single molecular target. Such drugs have limited symptomatic activities, and current pharmacological approaches have severe limitations in their ability to be neuroprotective and to modify the course of the disease, offering incomplete and transient benefit to patients. Yet in laboratory and animal models, a number of drugs have demonstrated the ability to be neuroprotective, but in clinical trials, they have failed as a form of symptomatic treatment and disease modification. This situation is not different from that of Parkinson's disease or amyotrophic lateral sclerosis, where the same problems exist. There are a number of valid reasons why we have failed to alter the course of these progressive neurodegenerative disorders. First and foremost, the models employed in vitro and in vivo are not true representations of complex disease as seen in man. Most of the effort has been in the direction of preventing the formation and overexpression of Abeta peptide in transgenic mice expressing Abeta peptide and plaques. Yet in these animals, there is no process of neurodegeneration. Yet one must question whether the disease is a disorder of Abeta-peptide-induced plaque formation resulting in the cognitive decline or if other processes are involved. The hope is that the newly developed rat transgenic model, which emulates many features of AD, will advance the pathological understanding of the disease and may lead to the development of new therapeutic strategies. The complex pathology of AD pathways includes changes in gene expression, protein metabolisms, response of receptors, level of neurotransmitters, activity of kinase, and signaling pathways. The most important events in neuroprotection and neuroregeneration are the selection of drugs that include synthetic products, natural products, amyloid synthesis, hormonal balance, and nanoparticles intended for a variety of biochemical targets such as oxidative stress. This special issue provides a new knowledge based on therapeutic candidates designed to act on multiple neural and biochemical targets involved in the neurodegenerative process and to possess neuroprotective and neurorestorative activities. Kiminobu Sugaya Moussa B. H. Youdim Agneta Nordberg K. S. Jagannatha Rao

Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease.

Aβ peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Aβ42 specifically in adult neurons, to avoid developmental effects. Aβ42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Aβ42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment) rescued Aβ42 toxicity. Aβ42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Aβ42. The GSK-3–mediated effects on Aβ42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Aβ42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Aβ42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Aβ42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.

A high throughput screen identifies compounds that inhibit Abeta peptide aggregation and reduce Abeta toxicity in vitro and in drosophila melanogaster

A high throughput screen identifies compounds that inhibit Abeta peptide aggregation and reduce Abeta toxicity in vitro and in drosophila melanogaster

Minding metals: Tailoring multifunctional chelating agents for neurodegenerative disease

Neurodegenerative diseases like Alzheimer's and Parkinson's disease are associated with elevated levels of iron, copper, and zinc and consequentially high levels of oxidative stress. Given the multifactorial nature of these diseases, it is becoming evident that the next generation of therapies must have multiple functions to combat multiple mechanisms of disease progression. Metal-chelating agents provide one such function as an intervention for ameliorating metal-associated damage in degenerative diseases. Targeting chelators to adjust localized metal imbalances in the brain, however, presents significant challenges. In this perspective, we focus on some noteworthy advances in the area of multifunctional metal chelators as potential therapeutic agents for neurodegenerative diseases. In addition to metal chelating ability, these agents also contain features designed to improve their uptake across the blood-brain barrier, increase their selectivity for metals in damage-prone environments, increase antioxidant capabilities, lower Abeta peptide aggregation, or inhibit disease-associated enzymes such as monoamine oxidase and acetylcholinesterase.

Receptor-associated Protein Interacts with Amyloid-β Peptide and Promotes Its Cellular Uptake

Brain amyloid-beta (Abeta) peptide accumulation and aggregation are critical events in the pathogenesis of Alzheimer disease. Increasing evidence has demonstrated that LRP1 is involved in Alzheimer disease pathogenesis. The physiological ligands of LRP1, including apoE, play significant roles in the cellular clearance of Abeta. The receptor-associated protein (RAP) is a specialized chaperone for members of the low density lipoprotein receptor family. RAP shares structural and receptor-binding properties with apoE. Here, we show that RAP binds to both Abeta40 and Abeta42 in a concentration-dependent manner and forms complexes with them. Fluorescence-activated cell sorter analysis showed that RAP significantly enhances the cellular internalization of Abeta in different cell types, including brain vascular smooth muscle, neuroblastoma, glioblastoma, and Chinese hamster ovary cells. This effect of RAP was confirmed by fluorescence microscopy and enzyme-linked immunosorbent assay. RAP binds to both LRP1 and heparin; however, the ability of RAP to enhance Abeta cellular uptake was blocked by heparin and heparinase treatment but not by LRP1 deficiency. Furthermore, the effects of RAP were significantly decreased in heparan sulfate proteoglycan-deficient Chinese hamster ovary cells. Our findings reveal that RAP is a novel Abeta-binding protein that promotes cellular internalization of Abeta.

Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer’s disease

Aluminum (Al) exposure has been reported to be a risk factor for Alzheimer's disease (senile dementia of Alzheimer type), although the role of Al in the etiology of Alzheimer's disease remains controversial. We examined the presence of Al in the Alzheimer's brain using energy-dispersive X-ray spectroscopy combined with transmission electron microscopy (TEM-EDX). TEM-EDX analysis allows simultaneous imaging of subcellular structures with high spatial resolution and analysis of small quantities of elements contained in the same subcellular structures. We identified senile plaques by observation using TEM and detected Al in amyloid fibers in the cores of senile plaques located in the hippocampus and the temporal lobe by EDX. Phosphorus and calcium were also present in the amyloid fibers. No Al could be detected in the extracellular space in senile plaques or in the cytoplasm of nerve cells. In this study, we demonstrated colocalization of Al and beta-amyloid (Abeta) peptides in amyloid fibers in the cores of senile plaques. The results support the following possibilities in the brains of patients with Alzheimer's disease: Al could be involved in the aggregation of Abeta peptides to form toxic fibrils; Al might induce Abeta peptides into the beta-sheet structure; and Al might facilitate iron-mediated oxidative reactions, which cause severe damage to brain tissues.

Modulation of aggregate size- and shape-distributions of the amyloid-β peptide by a designed β-sheet breaker

A peptide with 42 amino acid residues (Abeta42) plays a key role in the pathogenesis of the Alzheimer's disease. It is highly prone to self aggregation leading to the formation of fibrils which are deposited in amyloid plaques in the brain of diseased individuals. In our study we established a method to analyze the aggregation behavior of the Abeta peptide with a combination of sedimentation velocity centrifugation and enhanced data evaluation software as implemented in the software package UltraScan. Important information which becomes accessible by this methodology is the s-value distribution and concomitantly also the shape-distribution of the Abeta peptide aggregates generated by self-association. With this method we characterized the aggregation modifying effect of a designed beta-sheet breaker molecule. This compound is built from three head-to-tail connected aminopyrazole moieties and represents a derivative of the already described Tripyrazole. By addition of this compound to a solution of the Abeta42 peptide the maximum of the s-value distribution was clearly shifted to smaller s-values as compared to solutions where only the vehicle DMSO was added. This shift to smaller s-values was stable for at least 7 days. The information about size- and shape-distributions present in aggregated Abeta42 solutions was confirmed by transmission electron microscopy and by measurement of amyloid formation by thioflavin T fluorescence.

Evidence of TAU pathology in kaolin-induced hydrocephalus model of the aged rat

Background Accumulation of A-beta peptides and hyperphosphorylated Tau (hpTAU) has been observed in immunohistochemical (IHC) studies of kaolin-induced hydrocephalus in the aged rat. Defective clearance via CSF and altered transport via blood brain barrier receptor expressions was suggested to be causal [1]. The present study reports further evidence to the significance of A-beta and TAU pathology as disease mechanisms in hydrocephalus using quantitative A-beta and hpTAU ELISA in addition to IHC studies of the lipid oxygenase 12/15 enzyme (LOX12/15), a marker of the cytokine-induced inflammation in Alzheimer disease (AD).

A Molecular Dynamics Study on the Binding and Interaction of the Amyloid-Beta (1-42) Peptide with Phospholipid Bilayers

The Amyloid-Beta (A-Beta) peptide is a key aggregate species in Alzheimer's disease. While aspects of the A-Beta peptide aggregation pathway have previously been elucidated, the initial conversion of monomer peptides into an oligomer during aggregation is not clearly understood. One potential mediator of these early stages of aggregation is interactions of A-Beta with cell membranes, particularly anionic cell membranes. We use unconstrained and umbrella sampling molecular dynamics simulations to investigate interactions between the 42-amino acid A-Beta peptide and model bilayers consisting of zwitterionic dipalmitoylphophatidylcholine (DPPC) lipids and anionic dioleoylphosphatidylserine (DOPS) lipids. From this work, we determine that A-Beta binds to the surface of DPPC and DOPS bilayers over the small length scales used in simulations. Our results also support the hypothesis that the charge on the bilayer surface and on the peptide affects both the free energy of peptide-membrane binding and the distribution of the peptide on the bilayer surface. Finally, no significant secondary structure change is observed in the peptide during the timescales used in these simulations. This result may indicate all-atom simulation times are too short to observe secondary structure changes in this system or that structure change during the oligomerization process requires peptide-peptide interactions. Our work demonstrates that interactions between the A-Beta peptide and lipid bilayers promote a peptide distribution on the bilayer surface that is prone to peptide-peptide interactions, which can influence the propensity of A-Beta to aggregate into higher order structures.

Neurobiology of Alzheimer′s disease

Alzheimer's disease (AD) is a devastating neurodegenerative disease, the most common among the dementing illnesses. The neuropathological hallmarks of AD include extracellular β-amyloid (amyloid precursor protein (APP) deposits, intracellular neurofibrillary tangles (NFT)), dystrophic neuritis and amyloid angiopathy. The mismetabolism of APP and the defective clearance of β amyloid generate a cascade of events including hyperphosphorylated tau (τ) mediated breakdown of microtubular assembly and resultant synaptic failure which results in AD. The exact aetiopathogenesis of AD is still obscure. The preeminent hypotheses of AD include amyloid cascade hypothesis and tau hyperphosphorylation. The amyloid hypothesis states that extracellular amyloid plaques formed by aggregates of Aβ peptide generated by the proteolytic cleavages of APP are central to AD pathology. Intracellular assembly states of the oligomeric and protofibrillar species may facilitate tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction. The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Vascular hypothesis is also proposed for AD and it concludes that advancing age and the presence of vascular risk factors create a Critically Attained Threshold of Cerebral Hypoperfusion (CATCH) which leads to cellular and subcellular pathology involving protein synthesis, development of plaques, inflammatory response, and synaptic damage leading to the manifestations of AD. Multiple other aetiological and pathogenetic hypotheses have been put forward including genetics, oxidative stress, dysfunctional calcium homeostasis, hormonal, inflammatory-immunologic, and cell cycle dysregulation with the resultant neurotransmitter dysfunctions and cognitive decline. The available therapeutic agents target only the neurotransmitter dysfunction in AD and agents specifically targeting the pathogenetic mechanisms like amyloid deposition and tau hyperphosphorylation might provide a definite therapeutic edge.

FTIR spectroscopic studies on aggregation process of the β‐amyloid 11–28 fragment and its variants

Aggregation of Abeta peptides is a seminal event in Alzheimer's disease. Detailed understanding of the Abeta assembly process would facilitate the targeting and design of fibrillogenesis inhibitors. Here, conformational studies using FTIR spectroscopy are presented. As a model peptide, the 11-28 fragment of Abeta was used. This model peptide is known to contain the core region responsible for Abeta aggregation. The structural behavior of the peptide during aggregation provoked by the addition of water to Abeta(11-28) solution in hexafluoroisopropanol was compared with the properties of its variants corresponding to natural, clinically relevant mutants at positions 21-23 (A21G, E22K, E22G, E22Q and D23N). The results showed that the aggregation of the peptides proceeds via a helical intermediate, and it is possible that the formation of alpha-helical structures is preceded by creation of 3(10)-helix/3(10)-turn structures.

Formation of highly toxic soluble amyloid beta oligomers by the molecular chaperone prefoldin

Alzheimer's disease (AD) is a neurological disorder characterized by the presence of amyloid beta (Abeta) peptide fibrils and oligomers in the brain. It has been suggested that soluble Abeta oligomers, rather than Abeta fibrils, contribute to neurodegeneration and dementia due to their higher level of toxicity. Recent studies have shown that Abeta is also generated intracellularly, where it can subsequently accumulate. The observed inhibition of cytosolic proteasome by Abeta suggests that Abeta is located within the cytosolic compartment. To date, although several proteins have been identified that are involved in the formation of soluble Abeta oligomers, none of these have been shown to induce in vitro formation of the high-molecular-mass (> 50 kDa) oligomers found in AD brains. Here, we examine the effects of the jellyfish-shaped molecular chaperone prefoldin (PFD) on Abeta(1-42) peptide aggregation in vitro. PFD is thought to play a general role in de novo protein folding in archaea, and in the biogenesis of actin, tubulin and possibly other proteins in the cytosol of eukaryotes. We found that recombinant Pyrococcus PFD produced high-molecular-mass (50-250 kDa) soluble Abeta oligomers, as opposed to Abeta fibrils. We also demonstrated that the soluble Abeta oligomers were more toxic than Abeta fibrils, and were capable of inducing apoptosis. As Pyrococcus PFD shares high sequence identity to human PFD and the PFD-homolog protein found in human brains, these results suggest that PFD may be involved in the formation of toxic soluble Abeta oligomers in the cytosolic compartment in vivo.

GSK-3beta activation mediates Abeta induced tau pathology in multiple transgenic mice

Alzheimer's disease (AD) is a complex disorder neuropathologically characterized by extra- and/or intracellular aggregation of toxic Abeta peptide and tau protein species, neuroinflammation, neuronal and synaptic loss. Toxic Abeta species are considered to be upstream in the etiopathological mechanism. We could mimic all neuropathological characteristics except for the tau pathology in mutant V717I amyloid precursor protein (APP-V717I) overexpressing mice. This mutation causes a familial form of AD in patients. In order to have a more complete animal model we overexpressed APP-V717I and tau-P301L protein in mice. Tau-P301L causes hereditary frontotemporal dementia (FTD) in patients. Whereas the single transgenic APP-V717 and Tau-P301L transgenic mice developed amyloid and tau pathology (intraneuronal aggregation of tau protein), both pathologies were combined in the bigenic (biAT) mice. However, tau pathology was redistributed from the spinal cord and hindbrain to the forebrain in the bigenic mice as compared to the tau-P301L mice. Aggregated tau is invariably hyperphosphorylated. To investigate the contribution of tau phosphorylation in the development of tau pathology tau-P301L and the most important tau kinase, GSK-3beta, were co-overexpressed in mice (biGT mice). Strikingly, the tau pathology in the biGT mice was redistributed in a similar fashion in the biGT mice as in the biAT mice compared to the tau-P301L mice. It could be demonstrated as well that GSK-3beta activity in brain is increased as a consequence of APP overexpression. In a cellular model, tau expressing yeast, we could demonstrate that increased phosphorylation of tau causes a conformational change that starts tau aggregation. Together the data imply that toxic Abeta species cause kinase activation, increased tau phosphorylation, which subsequently leads to tau pathology. The mechanism by which Abeta causes activation of GSK-3beta is unknown. Currently we are investigating the possibility whether neuroinflammation is involved.

Reduced Membrane Lipids in the Cortex of Alzheimer’s Disease Transgenic Mice

Accumulating evidence suggests that the conversion of Abeta peptides to soluble, neurotoxic polymers is the key event in the development of Alzheimer's disease (AD). Moreover, interactions between Abeta peptides and neuronal membrane lipids likely play a vital role in developing the neurotoxicity associated with AD. The aim of this study is to assess whether lipid matrix of neuronal membranes is affected by the accumulation of Abeta peptides in double transgenic mouse model of AD expressing both mutant human beta-amyloid precursor protein (APP) and presenilin 1 (PS1). We apply high pressure liquid chromatography with an evaporative light scattering detector to compare levels of cholesterol, galactocerebrosides, and phospholipid subclasses simultaneously in cortex samples between AD double transgenic mice at 4 months of age when Abeta production and amyloid plaque deposition is just beginning and at 9 months, when there is advanced Abeta levels and plaque deposition compared to age-matched wild-type (B6/SJL) mice. Both cholesterol (CL) and phospholipids (PL) are significantly lower in 9-month-old AD mice than the same age of B6/SJL mice. Among PL subclasses, phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylcholine (PC) are selectively reduced in 9-month-old AD mice. The molar ratios of CL to PL in 9-month-old AD mice (1.19 +/- 0.27) were significantly higher than those of 9-month-old B6/SJL mice (0.81 +/- 0.08). In keeping with decreased levels of PL, there are also significant reductions of very long-chain n-3 fatty acids (docosahexaenoic acid) and n-6 fatty acid (arachidonic acid) in 9-month-old AD mice. On the other hand, ratios of total n-6 to total n-3 fatty acids were significantly higher in 9-month-old AD mice than in the same age of B6/SJL mice. Taken together, our present data support a role for the interactions of amyloid-beta peptide and neuronal membranes in the subsequent development of AD.

Suppression of in Vivo β-Amyloid Peptide Toxicity by Overexpression of the HSP-16.2 Small Chaperone Protein

Expression of the human beta-amyloid peptide (Abeta) in a transgenic Caenorhabditis elegans Alzheimer disease model leads to the induction of HSP-16 proteins, a family of small heat shock-inducible proteins homologous to vertebrate alphaB crystallin. These proteins also co-localize and co-immunoprecipitate with Abeta in this model (Fonte, V., Kapulkin, V., Taft, A., Fluet, A., Friedman, D., and Link, C. D. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 9439-9444). To investigate the molecular basis and biological function of this interaction between HSP-16 and Abeta, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses Abeta toxicity. Wild type Abeta-(1-42), but not Abeta single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Abeta in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but it did not reduce the overall accumulation of Abeta peptide or alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to Abeta in vitro, with a preferential affinity for oligomeric Abeta species. This interaction between Abeta and HSP-16.2 also influences the formation of Abeta oligomers in in vitro assays. These studies are consistent with a model in which small chaperone proteins reduce Abeta toxicity by interacting directly with the Abeta peptide and altering its oligomerization pathways, thereby reducing the formation of a minor toxic species.

Interaction between Alzheimer's Aβ1-42 Peptide and DNA Detected by Surface Plasmon Resonance

Alzheimer's disease is a form of senile mental disorder characterized by the presence of extracellular plaques, containing amyloid-beta (Abeta) as the main component. According to the amyloid hypothesis, an increase of extracellular Abeta production is in the origin of the aberrant plaques causing neuronal loss and dementia. However, a wealth of evidence has been accumulated pointing to the toxicity of soluble intracellular Abeta, having different morphologies of aggregation, as the origin of the neurodegenerative process. The exact nature of the initial molecular events by which Abeta exerts its neurotoxicity, remains obscure. Different forms of soluble Abeta peptide aggregates have been recently found to reside in the nucleus of CHO cells and Alzheimer's disease brain samples. This paper focus mainly on the interaction between DNA and the 42 residue Abeta (Abeta42) as studied by Surface Plasmon Resonance. Electronic microscopy and UV-visible spectroscopy are also used to further characterize the interaction. Particular attention is paid to the extent of Abeta42 aggregation needed to observe the interaction with DNA. Our results show that DNA binds all soluble aggregate forms of Abeta42, therefore suggesting that DNA binding is a general property of different soluble forms of Abeta42, unrelated to the extent of aggregation.

BACE Inhibitors as Potential Therapeutics for Alzheimers disease

Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Abeta is derived from a precursor protein by two sequential cleavage steps involving beta- and gamma-secretases, two proteolytic enzymes that represent rational drug targets. beta-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer's disease. In this review, we summarize current approaches towards the development of BACE inhibitors with focus on bioactive compounds and related patents. Recent reports have described drugs that are effective at inhibiting Abeta production in the brain of transgenic mouse models. The beginning of Phase I clinical trials has been approved for one of them and we can expect that in the near future BACE inhibitors will provide novel effective therapeutics to treat AD.