)Heinrich-Heine-Universit€ at D€ usseldorf, Institut f€ ur Physikalische Biologie and BMFZ, 40225 D€ usseldorf, Germany,^Forschungszentrum J€ ulich, ISB-2, 52425 J€ ulich AbstractSeveral lines of evidence suggest that the amyloid-β-peptide (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). Not only Aβ fibrils but also small soluble Aβ oligomers in particular are suspected to be the major toxic species responsible for disease development and progression. The present study reports on in vitro and in vivo properties of the Aβ targeting D-enantiomeric amino acid peptide D3. We show that next to plaque load and inflammation reduction, oral application of the peptide improved the cognitive performance of AD transgenic mice. In addition, we provide in vitro data elucidating the potential mechanism underlying the observed in vivo activity of D3. These data suggest that D3 precipitates toxic Aβ species and converts them into nonamyloidogenic, nonfibrillar, and nontoxic aggregates without increasing the concentration of monomeric Aβ. Thus, D3 exerts an interesting and novel mechanism of action that abolishes toxic Aβ oligomers and thereby supports their decisive role in AD development and progression.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, affecting more than 20 million people world‐wide. Only palliative therapies are available today. We identified a novel D‐enantiomeric amino acid peptide “D3” with significant Aβ disaggregation and Aβ aggregation inhibiting properties in vitro an in vivo. It inhibits cytotoxicity in cell culture and reduces amyloid plaque load and cerebral damage of transgenic AD mouse models. D3 might be a tool for further research approaches on the origin of AD and might provide a novel basis for therapeutic and preventive approaches to AD.
Small heat shock proteins translocate to unfolded titin Ig domains under stress conditions to prevent titin aggregation and myocyte stiffening.
In a variety of normal and pathological cell types, Rho-kinases I and II (ROCKI/II) play a pivotal role in the organization of the nonmuscle and smooth muscle cytoskeleton and adhesion plaques as well as in the regulation of transcription factors. Thus, ROCKI/II activity regulates cellular contraction, motility, morphology, polarity, cell division, and gene expression. Emerging evidence suggests that dysregulation of the Rho-ROCK pathways at different stages is linked to cardiovascular, metabolic, and neurodegenerative diseases as well as cancer. This review focuses on the current status of understanding the multiple functions of Rho-ROCK signaling pathways and various modes of regulation of Rho-ROCK activity, thereby orchestrating a concerted functional response.
We investigated the therapeutic effects of two different versions of A 1-15 (16) liposome-based vaccines. Inoculation of APP-V717IxPS-1 (APPxPS-1) double-transgenic mice with tetrapalmitoylated amyloid 1-15 peptide (palmA 1-15), or with amyloid 1-16 peptide (PEG-A 1-16) linked to a polyethyleneglycol spacer at each end, and embedded within a liposome membrane, elicited fast immune responses with identical binding epitopes. PalmA 1-15 liposomal vaccine elicited an immune response that restored the memory defect of the mice, whereas that of PEG-A 1-16 had no such effect. Immunoglobulins that were generated were predominantly of the IgG class with palmA 1-15, whereas those elicited by PEG-A 1-16 were primarily of the IgM class. The IgG subclasses of the antibodies generated by both vaccines were mostly IgG2b indicating noninflammatory Th2 isotype. CD and NMR revealed predominantly -sheet conformation of palmA1-15 and random coil of PEG-A 1-16. We conclude that the association with liposomes induced a variation of the immunogenic structures and thereby different immunogenicities. This finding supports the hypothesis that Alzheimer's disease is a ''conformational'' disease, implying that antibodies against amyloid sequences in the -sheet conformation are preferred as potential therapeutic agents.Alzheimer's disease ͉ -amyloid ͉ vaccine C linical manifestations of Alzheimer's disease (AD) include progressive memory loss, cognitive impairment, confusion, and personality changes. The major neuropathological changes in the brains of AD patients are senile plaques and neurofibrillar tangles causing progressive neuronal dysfunction. These pathological alterations are likely causally involved in eventual neuronal death, particularly in brain regions related to memory and cognition (1-4). Senile plaques are formed predominantly by the -amyloid peptide A 1-42 that is coiled and ␣-helical in its soluble form but, upon conformational transition, aggregates into -sheeted multimers. The monomeric A peptide is a physiological metabolite of the large amyloid precursor protein (APP, 695-770 aa) that undergoes processing by several sequential proteolytic steps (5). The A 1-42 aggregates are proposed to play the key role in the pathogenesis of AD (6). In transgenic animals that overexpress mutant human APP, anti-A-specific antibodies decreased the A burden and improved memory after either passive (7-11) or active (12-18) immunization.We previously demonstrated that i.p. inoculation of tetrapalmitoylated A1-16 reconstituted in liposomes to transgenic NORBA mice elicited significant titers of anti-A antibodies, that solubilized amyloid fibers in vitro and pancreatic A plaques in vivo (19). To circumvent T cell-mediated immune responses known to be causatively involved in the adverse events of meningoencephalitis of AD patients immunized with A1-42 (20-22), the A1-16 and 1-15 sequences were used for immunization of APPxPS1 double-transgenic mice (23) because strong T cell epitopes are located more toward the C-te...
The conversion of the ␣-helical, cellular isoform of the prion protein (PrP C ) to the insoluble, -sheet-rich, infectious, diseasecausing isoform (PrP Sc ) is the key event in prion diseases. In an earlier study, several forms of PrP were converted into a fibrillar state by using an in vitro conversion system consisting of low concentrations of SDS and 250 mM NaCl. Here, we characterize the structure of the fibril precursor state, that is, the soluble state under fibrillization conditions. CD spectroscopy, analytical ultracentrifugation, and chemical cross-linking indicate that the precursor state exists in a monomer-dimer equilibrium of partially denatured, ␣-helical PrP, with a well defined contact site of the subunits in the dimer. Using fluorescence with thioflavin T, we monitored and quantitatively described the kinetics of seeded fibril formation, including dependence of the reaction on substrate and seed concentrations. Exponential, seed-enhanced growth can be achieved in homogeneous solution, which can be enhanced by sonication. From these data, we propose a mechanistic model of fibrillization, including the presence of several intermediate structures. These studies also provide a simplified amplification system for prions.dimer ͉ seeding ͉ fibril ͉ precursor state
The deposition of amyloid in brain tissue in the context of neurodegenerative diseases involves the formation of intermediate species-termed oligomers-of lower molecular mass and with structures that deviate from those of mature amyloid fibrils. Because these oligomers are thought to be primarily responsible for the subsequent disease pathogenesis, the elucidation of their structure is of enormous interest. Nevertheless, because of the high aggregation propensity and the polydispersity of oligomeric species formed by the proteins or peptides in question, the preparation of appropriate samples for high-resolution structural methods has proven to be rather difficult. This is why theoretical approaches have been of particular importance in gaining insights into possible oligomeric structures for some time. Only recently has it been possible to achieve some progress with regard to the experimentally based structural characterization of defined oligomeric species. Here we discuss how theory and experiment are used to determine oligomer structures and what can be done to improve the integration of the two disciplines.
Strong evidence exists for a central role of amyloid β-protein (Aβ) oligomers in the pathogenesis of Alzheimer’s disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aβ aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAβ3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aβ aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease.
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