Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease

Mitochondria contribute to shape intraneuronal Ca2+ signals. Excessive Ca2+ taken up by mitochondria could lead to cell death. Amyloid beta (A beta) causes cytosolic Ca2+ overload, but the effects of A beta on mitochondrial Ca2+ levels in Alzheimer's disease (AD) remain unclear. Using a ratiometric Ca2+ indicator targeted to neuronal mitochondria and intravital multiphoton microscopy, we find increased mitochondrial Ca2+ levels associated with plaque deposition and neuronal death in a transgenic mouse model of cerebral beta -amyloidosis. Naturally secreted soluble A beta applied onto the healthy brain increases Ca2+ concentration in mitochondria, which is prevented by blockage of the mitochondrial calcium uniporter. RNA-sequencing from post-mortem AD human brains shows downregulation in the expression of mitochondrial influx Ca2+ transporter genes, but upregulation in the genes related to mitochondrial Ca2+ efflux pathways, suggesting a counteracting effect to avoid Ca2+ overload. We propose lowering neuronal mitochondrial Ca2+ by inhibiting the mitochondrial Ca2+ uniporter as a novel potential therapeutic target against AD. Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral beta -amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular A beta oligomers and the mitochondrial calcium uniporter

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Fair value accounting in the agricultural sector: some implications for international accounting harmonization

In a recent issue of this journal, Argiles and Slof (2001) analysed the main features of the European Farm Accountancy Database Network (FADN) against the backdrop of IAS 41, the new international accounting standard on agriculture, and arrived at the conclusion that FADN offers an excellent tool for operationalizing IAS 41 in European farms. The present study revisits some of the key issues in Argiles and Slof's paper in a wider international context and highlights their implications for the harmonization of farm accounting practices around the world. In particular, this paper contends that there are some key provisions of IAS 41 that are incompatible with the European Union Fourth Directive which Argiles and Slof (2001, p. 364) apparently overlooked by focusing only on aspects of the directive that sanction current value measurement and ignoring those that relate to the treatment of associated holding gains or losses. Furthermore, this paper also demonstrates that Argiles and Slof's argument that simplicity is another improvement of IAS 41 vis-a-vis the French Plan Comptable General Agricole is flawed. Indeed, it is shown here that it would be virtually impossible to implement IAS 41 in Francophone countries in the absence of a fundamental revision, if not complete abandonment, of the plan comptable, at least in view of major conceptual differences between the notions of income, production and value added espoused by national statisticians and those enshrined in IAS 41.