Alzheimer's disease

Regulation of NMDA receptor trafficking by amyloid β. Snyder, E. M. et al. Nature Neurosci. 8, 1051–1058 (2005)

Tau suppression in a neurodegenerative mouse model improves memory function. SantaCruz, K. et al. Science 309, 476–481 (2005)

Two recent papers shed new light on the pathological processes involved in neurodegenerative diseases. Snyder and colleagues provide evidence for the synaptic amyloid β (Aβ) hypothesis of Alzheimer's disease by showing that non-fibrillar Aβ acts at synapses and disrupts glutamergic transmission. Addition of Aβ42 to corticol neurons in culture promoted the endocytosis of N-methyl-D-aspartate (NMDA) receptors, reducing long-term potentiation (LTP) and therefore decreasing the synaptic plasticity required for memory and learning. In the second paper, SantaCruz et al. studied the role of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein in neurodegeneration. The authors used mice expressing a tau variant that can be suppressed with doxycycline and found that expression of the tau variant in mice causes NFTs, neuronal loss and behavioural defects such as memory loss. Suppression of tau with doxycycline resulted in recovery of memory loss and neuron numbers despite the continued accumulation of NFTs.

Anti-thrombotics

Defective thrombus formation in mice lacking coagulation factor XII. Renné, T. et al. J. Exp. Med. 202, 271–281 (2005)

Coagulation factor XII (FXII), a protein not previously considered as important for blood coagulation in humans, has now emerged as a potential drug target for anti-thrombotic drugs. Renné et al. used three mouse models of platelet recruitment and thrombus formation and found that mice lacking FXII have a severe defect in the formation and stabilization of platelet-rich occlusive thrombi, and are also protected against thromboembolism brought on by the administration of collagen or adrenaline. Restoring FXII function by infusing human FXII into the mice restored their ability to form thrombi. These initial studies suggest further investigation of the role of FXII in human thrombus formation is warranted.

Inflammation

Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. Thiel, M. et al. PLoS Biol. 3, e174 (2005)

This study, carried out using mouse models of lung infection, suggests that the use of high oxygen concentrations to treat acute respiratory distress syndrome in humans might actually worsen the condition by interfering with a hypoxia-driven anti-inflammatory pathway involving the adenosine A2A receptor. The authors proposed that oxygen-mediated inhibition of the hypoxia–adenosine–A2A-receptor pathway caused a lack of endogenously formed adenosine, which has recently been shown to downregulate inflammation. Administration of an A2A receptor agonist restored the lack of adenosine and prevented further inflammation in the inflamed lungs of oxygenated mice.