Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kd) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kd inhibition confers protection in ischaemia/ reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kd inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kd (p110d D910A/D910A ) or wild-type mice pre-or post-treated with the PI3Kd inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kd as a potential therapeutic target in ischaemic stroke.

Dysphagia in inclusion body myositis (IBM) is common and associated with increased mortality and morbidity due to aspiration pneumonia, malnutrition and dehydration. There is currently no consensus on treatment of dysphagia in IBM and outcomes are variable depending on timing of intervention, patient preference and available expertise. There is a paucity of research exploring the pathophysiology of dysphagia in IBM and appropriate investigations. Increased knowledge of the aetiopathogenesis is likely to change the approach to treatment as well as improve the quality of life for patients. This review explores the epidemiology and pathophysiology of dysphagia in IBM and the currently available treatment strategies.

Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-␤ (A␤) peptide. Accumulation of A␤, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored. Here, we report that inactivation of the p110␦ isoform of phosphoinositide 3-kinase (PI3K) reduces anterograde axonal trafficking of APP in hippocampal neurons and dampens secretion of the inflammatory cytokine tumor necrosis factor-alpha by microglial cells in the familial AD APP swe /PS1 ⌬E9 (APP/PS1) mouse model. Moreover, APP/PS1 mice with kinase-inactive PI3K␦ (␦ D910A) had reduced A␤ peptides levels and plaques in the brain and an abrogated inflammatory response compared with APP/PS1 littermates. Mechanistic investigations reveal that PI3K␦ inhibition decreases the axonal transport of APP by eliciting the formation of highly elongated tubular-shaped APP-containing carriers, reducing the levels of secreted A␤ peptide. Importantly, APP/PS1/␦ D910A mice exhibited no spatial learning or memory deficits. Our data highlight inhibition of PI3K␦ as a new approach to protect against AD pathology due to its dual action of dampening microglial-dependent neuroinflammation and reducing plaque burden by inhibition of neuronal APP trafficking and processing.

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