Dementia is a syndrome characterized by loss of memory and cognitive functions. The most common type of dementia is Alzheimer’s disease (AD), accounting for 60%-80% of all cases. According to the World Alzheimer Report 2010, AD has a dramatic impact on the global economy with an estimated worldwide cost of 604 billion of dollars in 2010. This means that if AD care were a country, it would be the world’s 18th largest economy, exceeding countries like Belgium and Sweden. The dramatic socioeconomic impact of AD is foreseen to worsen in the near future. Indeed, these figures will triple by 2050 unless a cure that delays onset or progression of the disease is found. AD causes a large loss of neurons and synapses in the brain, leading to an overall loss in brain weight. Pathogenesis of the disease is still not fully understood. Nevertheless, the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles are considered hallmarks of the pathology. Aβ derives from the proteolytic processing of a transmembrane protein, namely the amyloid protein precursor (APP). The proteolytic cleavage of APP has been considered for years as a major therapeutic target in AD, and a number of molecules inhibiting this process have been developed as potential drugs. All of them has failed in clinical trials, occasionally leading to severe side effects in human. This failure highlighted the need for a better understanding of the molecular basis of the disease and new therapeutic targets.
Apart from the amyloid basis of the disease, there is a growing evidence that neuroinflammation is strongly associated with neuron loss in AD and other neurodegenerative diseases. The accumulation of Aβ oligomers initiates an inflammatory response involving the activation of microglia that begin to produce pro-inflammatory cytokines, such as TNFα, ultimately leading to neuronal death. In support of this evidence, antiinflammatory drugs have been shown to have beneficial effects in slowing the progression of AD. The main aim of this study is to test the function and mechanism of a novel inflammatory protein, iRhom2, in AD.
iRhom2 has a clear link to TNFα, which is a pro-inflammatory cytokine with an emerging crucial role in neuroinflammation and progression of AD. TNFα is also an example for membrane proteins which undergo proteolysis at the cell surface, the so called ectodomain shedding. Release of soluble TNFα from the cell surface is mostly mediated by the TNFα converting enzyme (TACE), a member of disintegrin metalloproteinases (also known as ADAM17). TNFα is essential for innate immunity, but its deregulated generation is associated with several immune diseases, including rheumatoid arthritis, atherosclerosis and Crohn’s disease.The endoplasmic reticulum-associated protein iRhom2 is essential for maturation of TACE and its transport to the plasma membrane in immune cells, specifically in macrophages. Due to its ability to support TACE maturation, ablation of iRhom2 in mice led to decreased generation of soluble TNFα and defects in initiating immune responses. On the other hand, lack of iRhom2 is protective in autoimmune diseases, such as rheumatoid arthritis. Furthermore, iRhom2 has been recently identified as a genetic risk factor in AD. The improvement of inflammatory diseases upon iRhom2 ablation renders iRhom2 an attractive target to study during neuroinflammation in AD and a potential candidate for future therapies targeting neuroinflammation. Investigating the role of iRhom2 in neuroinflammation and progression of AD is the central objective of this study.
