Alzheimer's disease: synaptic dysfunction and Aβ

Synapse loss is an early and invariant feature of Alzheimer's disease (AD) and there is a strong correlation between the extent of synapse loss and the severity of dementia. Accordingly, it has been proposed that synapse loss underlies the memory impairment evident in the early phase of AD and that since plasticity is important for neuronal viability, persistent disruption of plasticity may account for the frank cell loss typical of later phases of the disease. Extensive multi-disciplinary research has implicated the amyloid β-protein (Aβ) in the aetiology of AD and here we review the evidence that non-fibrillar soluble forms of Aβ are mediators of synaptic compromise. We also discuss the possible mechanisms of Aβ synaptotoxicity and potential targets for therapeutic intervention

Visible light promoted photocatalytic water oxidation:effect of metal oxide catalyst composition and light intensity

A range of low cost nanoparticulate mixed transition metal oxides were prepared using a simple methodology and used as catalysts in visible light promoted water oxidations. The effect of catalyst and daylight equivalent light intensities on reaction efficiency in terms of O2 yields, TOF and proton production was determined

A vicious cycle of β amyloid-dependent neuronal hyperactivation

beta-amyloid (A beta)-dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer's disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of A beta-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to A beta-mediated hyperactivation. A beta-containing AD brain extracts and purified A beta dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of A beta-dependent neuronal dysfunction that can be active before plaque formation

Enhanced Proteolysis of β-Amyloid in APP Transgenic Mice Prevents Plaque Formation, Secondary Pathology, and Premature Death

AbstractConverging evidence suggests that the accumulation of cerebral amyloid β-protein (Aβ) in Alzheimer's disease (AD) reflects an imbalance between the production and degradation of this self-aggregating peptide. Upregulation of proteases that degrade Aβ thus represents a novel therapeutic approach to lowering steady-state Aβ levels, but the consequences of sustained upregulation in vivo have not been studied. Here we show that transgenic overexpression of insulin-degrading enzyme (IDE) or neprilysin (NEP) in neurons significantly reduces brain Aβ levels, retards or completely prevents amyloid plaque formation and its associated cytopathology, and rescues the premature lethality present in amyloid precursor protein (APP) transgenic mice. Our findings demonstrate that chronic upregulation of Aβ-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo

Chelate stabilized metal oxides for visible light photocatalyzed water oxidations

Lactate-stabilized calcium manganese oxide and cobalt hydroxide nanoparticles were utilized as catalysts in visible light photocatalyzed water oxidations. Chelated bi-metallic catalysts captured decomposed cobalt based electron acceptor and gave prolonged two stage reactions. Hydroxylated Co–lactates gave high TOF and O2 yields. Chelation produced extended reactions, higher yields and reduced waste.</p

Quantifying fine-sediment sources in primary and selectively logged rainforest catchments using geochemical tracers

Detailed information on post-logging sediment dynamics in tropical catchments is required for modelling downstream impacts on communities and ecosystems. Sediment tracing methods, which are potentially useful in extending to the large catchment scale and longer time scales, are tested in primary and selectively logged rainforest catchments of Sabah, Borneo. Selected nutrient (P and N) and trace metal (Ni and Zn) concentrations are shown to discriminate surface, shallow subsurface and deep subsurface sediment sources. Analysis of channel-stored fine-sediment samples and use of an unmixing model allow the relative importance of these vertical sediment sources to be estimated and erosion processes to be inferred for catchments of contrasting size

Visible light promoted photocatalytic water oxidation:proton and electron collection: via a reversible redox dye mediator

A quinone analogue as reversible electron and proton collector in visible light promoted water oxidations was investigated. Reagents were incorporated into microporous silica with surface absorbed cobalt catalyst. Reversible storage molecules are an important step towards solar fuels.</p

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

Evidence for a central role of amyloid β-protein (Aβ) in the genesis of Alzheimer’s disease (AD) has led to advanced human trials of Aβ-lowering agents. The “amyloid hypothesis” of AD postulates deleterious effects of small, soluble forms of Aβ on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aβ could be therapeutically advantageous, it is important to understand the full range of soluble Aβ derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aβ species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aβ40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aβ-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aβ. These N-terminally extended Aβ-containing monomeric fragments are distinct from soluble Aβ oligomers formed from Aβ1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing β-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site