Targeting metals rescues the phenotype in an animal model of tauopathy.

Tauopathies are characterized by the pathological accumulation of the microtubule associated protein tau within the brain. We demonstrate here that a copper/zinc chaperone (PBT2, Prana Biotechnology) has rapid and profound effects in the rTg(tauP301L)4510 mouse model of tauopathy. This was evidenced by significantly improved cognition, a preservation of neurons, a decrease in tau aggregates and a decrease in other forms of "pathological" tau (including phosphorylated tau and sarkosyl-insoluble tau).

Rabies screen reveals GPe control of cocaine-triggered plasticity.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area.

Oligomers, fact or artefact? SDS-PAGE induces dimerization of β-amyloid in human brain samples.

The formation of low-order oligomers of β-amyloid (Aβ) within the brain is widely believed to be a central component of Alzheimer's disease (AD) pathogenesis. However, despite advances in high-throughput and high-resolution techniques such as xMAP and mass spectrometry (MS), investigations into these oligomeric species have remained reliant on low-resolution Western blots and enzyme-linked immunosorbent assays. The current investigation compared Aβ profiles within human cortical tissue using sodium dodecyl sulphate (SDS) polyacrylamide gel electrophoresis (PAGE), xMAP and surface enhanced laser desorption/ionization time-of-flight MS and found that whilst there was significant correlation across the techniques regarding levels of monomeric Aβ, only SDS-PAGE was capable of detecting dimeric isoforms of Aβ.

Elucidating the role of metals in Alzheimer's disease through the use of Surface-Enhanced Laser Desorption/Ionisation time-of-flight mass spectrometry.

Alzheimer's disease (AD) is a highly heterogeneous and progressive dementia which is characterised by a progressive decline in cognitive functioning, selective neuronal atrophy, and loss of cortical volume in areas involved in learning and memory. However, recent research has indicated that the AD-affected brain is also besieged by increases in oxidative stress as well as perturbations to the homeostasis of biometals, such as copper and iron. These metals are known to interact with the neuropathological hallmark of AD, the β-amyloid peptide (Aβ), in a manner which increases Aβ's neurotoxic effects.

Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation.

Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-beta (Abeta) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3beta (GSK3beta) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3beta. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3beta through activation of an Akt signaling pathway.

Amyloid-beta peptide (Abeta) neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity.

Alzheimer's disease is an age-related neurodegenerative disorder with its toxicity linked to the generation of amyloid-beta peptide (Abeta). Within the Abeta sequence, there is a systemic repeat of a GxxxG motif, which theoretical studies have suggested may be involved in both peptide aggregation and membrane perturbation, processes that have been implicated in Abeta toxicity. We synthesized modified Abeta peptides, substituting glycine for leucine residues within the GxxxG repeat motif (GSL peptides).

Analysis of Abeta interactions using ProteinChip technology.

Abeta peptides are now acknowledged to play a central role in the pathogenesis of Alzheimer's disease. Their generation results from the sequential cleavage of amyloid precursor protein by beta and gamma secretases. The resulting peptide fragments impart toxicity via their ability to form soluble oligomers and bind to cell membranes.

Dimeric structures of alpha-synuclein bind preferentially to lipid membranes.

There is substantial evidence which implicates alpha-synuclein and its ability to aggregate and bind vesicle membranes as critical factors in the development of Parkinson's disease. In order to investigate the interaction between alpha-synuclein wild type (Wt) and its familial mutants, A53T and A30P with lipid membranes, we developed a novel lipid binding assay using surface enhanced laser desorption/ionisation-time of flight-mass spectrometry (SELDI-TOF MS). Wt and A53T exhibited similar lipid binding profiles; monomeric species and dimers bound with high relative affinity to the lipid surface, the latter of which exhibited preferential binding.