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iRhom2 in AD Report Summary

Project ID: 658061
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - iRhom2 in AD (iRhom2 in neuroinflammation and pathogenesis of Alzheimer’s Disease)

Reporting period: 2015-12-01 to 2017-11-30

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

"iRhom2 is a member of the ""inactive rhomboid"" family of pseudoenzymes, which are intramembrane serin proteases that lost their catalytic potential during evolution. Similarly to iRhom2, the other member of the family, iRhom1, functions as a TACE chaperone and supports its maturation. iRhom1 and iRhom2 are both ubiquitously expressed in all tissues, with the exception of immune cells, where only iRhom2 is expressed. This specific pattern of expression restricted to immune cells makes TACE activity, and subsequently TNFα release, specifically iRhom2-dependent and renders iRhom2 a specific target in neuroinflammation.
This study consisted of two major objectives:
1. Investigating the role of iRhom2 in the pathogenesis of AD. We have ablated iRhom2 in a well established murine model of AD that has an increased Aβ production, amyloid plaque deposition and strong neuroinflammation, with microglia activation and cytokine release, including TNF. We found that loss of iRhom2 mouse ameliorated AD pathology in this mouse model, with a clear decrease of deposited amyloid and improved reversal learning in behavioural tests (Fig 1A). In addition, we found that microglia in mice lacking iRhom2 developed specific features, including a decreased number of activated cells clustering around the plaques (microglia nodules) and microglia in a ""resting"" state (Fig 1B).
2. Identification of iRhom2/TACE substrates in macrophages. Cleavage of TNFα at the cell surface is a clear example of ectodomain shedding. Indeed, TNFα is synthesised as a transmembrane protein and needs to be proteolytically released by TACE in order to trigger immune responses. Macrophages lacking iRhom2, and therefore TACE activity, release reduced levels of TNFα. We investigated if shedding of other proteins additionally to TNFα could be reduced in macrophages lacking iRhom2. By using cutting-edge proteomics we identified an heterogeneous group of over 20 type-1 transmembrane proteins whose shedding was reduced when iRhom2 was inactivated (Fig 1C). Among them there were signalling receptors, phagocytic receptors and adhesion molecules. A number of these proteins were novel TACE substrates that, consequently, uncovered new functions of this enzyme in immune cells. Other identified substrates have a clear link to AD and microglia patho-physyiology, including the AD genetic risk factor TREM2."

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

"Alzheimer's is a terrible disease with currently no cure. In this study, we identified iRhom2 as a novel therapeutic target in AD and we are currently working on specific molecules targeting iRhom2 that may be potentially used in the therapy of Alzheimer's. In addition, we identified a number of proteins that are shed in an iRhom2-dependent manner in macrophages, thus uncovering new functions of iRhom2 in the immune system. We are currently preparing manuscripts to disseminate these results. In addition to great research data, Dr. Scilabra has gained new expertise in proteomics and animal models, which broadened his strong background in biochemistry. During the fellowship, Dr. Scilabra attended several courses, including ""lab management"" and ""intellectual property"". He was involved in the supervision of students, grant applications and he was appointed as peer-reviewer by editors of international journals. Finally, he has broadened his web of collaborations by participating to foremost conferences in the field. Altogether, these activities enhanced his lab leading awareness and will help him to accomplish his major objective of establishing his own independent research group in neurobiology."

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