Amyloid fibrils commonly exhibit multiple distinct morphologies in electron microscope and atomic force microscope images, often within a single image field. By using electron microscopy and solid-state nuclear magnetic resonance measurements on fibrils formed by the 40-residue beta-amyloid peptide of Alzheimer's disease (Abeta(1-40)), we show that different fibril morphologies have different underlying molecular structures, that the predominant structure can be controlled by subtle variations in fibril growth conditions, and that both morphology and molecular structure are self-propagating when fibrils grow from preformed seeds. Different Abeta(1-40) fibril morphologies also have significantly different toxicities in neuronal cell cultures. These results have implications for the mechanism of amyloid formation, the phenomenon of strains in prion diseases, the role of amyloid fibrils in amyloid diseases, and the development of amyloid-based nano-materials.

Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL͞6 mice are maintained on an intermittent fasting (alternateday fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.caloric restriction ͉ hippocampus ͉ insulin ͉ ␤-hydroxybutyrate ͉ ketosis

Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.

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In addition to neurological deficits, Huntington's disease (HD) patients and transgenic mice expressing mutant human huntingtin exhibit reduced levels of brain-derived neurotrophic factor, hyperglycemia, and tissue wasting. We show that the progression of neuropathological (formation of huntingtin inclusions and apoptotic protease activation), behavioral (motor dysfunction), and metabolic (glucose intolerance and tissue wasting) abnormalities in huntingtin mutant mice, an animal model of HD, are retarded when the mice are maintained on a dietary restriction (DR) feeding regimen resulting in an extension of their life span. DR increases levels of brain-derived neurotrophic factor and the protein chaperone heat-shock protein-70 in the striatum and cortex, which are depleted in HD mice fed a normal diet. The suppression of the pathogenic processes by DR in HD mice suggests that mutant huntingtin promotes neuronal degeneration by impairing cellular stress resistance, and that the body wasting in HD is driven by the neurodegenerative process. Our findings suggest a dietary intervention that may suppress the disease process and increase the life span of humans that carry the mutant huntingtin gene.is an inherited neurodegenerative disorder characterized by degeneration of neurons in the striatum and cerebral cortex resulting in abnormal involuntary movements (chorea), and psychiatric and cognitive abnormalities (1). The genetic defect involves expansion of CAG trinucleotide repeats in exon 1 of the HD gene resulting in polyglutamine expansions in the huntingtin protein (2-4). Neither the normal function of huntingtin nor the mechanism whereby polyglutamine expansions result in selective loss of striatal neurons is known, although impaired energy metabolism (5, 6), excitotoxicity (7), and oxidative stress (8) are implicated. It has been proposed that the mutant huntingtin causes neuronal dysfunction and death by altering the transcription of certain genes, including those encoding neurotransmitters and neurotrophic factors (9). Transgenic mice expressing polyglutamine expanded full-length or N-terminal fragments of huntingtin exhibit neurodegenerative changes in the striatum, progressive motor dysfunction, and premature death (10, 11). Oxidative stress and apoptosis are suggested in the pathogenic process because antioxidants (12) and caspase inhibitors (13) can slow disease progression in huntingtin mutant mice.Deficits in striatal and cortical glucose metabolism precede the appearance of symptoms in HD patients (14-16). Many HD patients and huntingtin mutant mice also exhibit hyperglycemia, apparently as the result of decreased insulin production and͞or sensitivity (17,18). A deficit in cellular energy metabolism may contribute to disease onset and progression because administration of creatine, an agent that reduces ATP depletion, delays the onset of symptoms and increases the survival times of huntingtin mutant mice (19). Another alteration in HD is decreased production of brain-derived neurotrophic factor (BDNF) (...

By covalently connecting taxol with a motif that is prone to self-assemble, we successfully generate the precursor (5a), the hydrogelator (5b), and hydrogel of a taxol derivative without compromising the cytotoxic activity of the taxol. This approach promises a general method to create nanofibers of therapeutic molecules that have a dual role, as both the delivery vehicle and the drug itself.

Aggregation in poor solvents and complexation with calf thymus DNA and bovine serum albumin turn "on" the fluorescence of tetraphenylethylene derivatives, due to the restriction of intra-molecular rotations of the dyes in the aggregates and complexes.

Self-assembly, a fundamental process at all scales, [1] plays a vital role in nature and provides an important guidance for design and fabrication of functional materials. [2] Particularly, self-assembly provides an attractive and practical methodology for creating artificial nanostructures that promise broad impacts and applications in the emerging field of nanoscience. For example, self-assembled nanoparticles can lead to novel optical materials [3] and high-density magnetic recording media; [4] self-assembled monolayers [5] have enabled nanometer thickness organic films to be constructed on a variety of substrates for modeling biological surface to control the fate of cells, [6] building molecular electronic devices, [7] developing nanolithography, [8] and generating nanostructures for biomedical diagnostics; [9] and the self-assembly of oligopeptides [10,11] and other organic molecules [12] has resulted in nanofibers as the functional matrices of hydrogels that find possible applications in tissue engineering, [10,13] inhibitor screening, [14] and wound healing. [15] Although these works reflect the exciting and important development of self-assembled nanostructures in a non-biological arena or extracellular settings, intracellular creation of artificial nanostructures remains less explored and its subsequent biological effects largely unknown despite of its potential significances and applications.To explore intracellular artificial nanostructures is significant for several reasons. First, self-assembled nanostructures (e.g., cell membranes, strands of nucleic acids, actin filaments) prevail in living cells and are indispensable for critical cellular functions (e.g., as structural motifs for maintaining integrity of cells, as effective storages for keeping genetic information, and as active devices for regulating numerous cellular processes), therefore intracellular artificial nanostructures provide an attractive and effective strategy from perturbing the cellular activities to managing the behaviors of cells. Second, many diseases are related to mishaps in cellular nanostructures (e.g., mismatch of base pairs, formation of b-amyloid, and misfolding of proteins), hence intracellular artificial nanostructures offers a versatile and accessible platform for mimicking, modeling, and understanding the mechanism of diseases. Third, spectacular advances in molecular cell biology (i.e., the study of biological process at the molecular level) during the last five decades have led to new insights into the evolution of life forms, and now there is a need to correlate biological process beyond molecule level and to understand structure and dynamics as a system (i.e., system biology). Self-assembled intracellular artificial structures at the nanoscale lend a convenient means to examine the structure and dynamics of cellular functions and to allow previously unconnected domains of knowledge to be understood at new levels of complexity.Intracellular artificial nanostructures can result from different methodologies, ...