Pathways linking Alzheimer’s disease risk genes expressed highly in microglia

Abstract

Microglia in the brain are exquisitely vigilant to their surroundings. They are dispersed throughout the brain parenchyma where they continually receive and integrate large numbers of incoming signals. They become activated once a tightly controlled signalling threshold is reached. This can lead to a cascade of cellular and molecular changes culminating in the recognition and engulfment of self and non-self structures ranging from macromolecules to whole cells depending on the initiating signal. Once internalised, they digest and where appropriate, present antigens to aid future recognition of pathogens. Their response to pathogenic signals in diseases such as Alzheimer’s disease (AD) has long been recognised, but recent genetic findings have cemented their direct causal contribution to AD and thus the potential to target them or their effector pathways as a possible treatment strategy. Around 25% of the ~84 AD risk genes have enriched or exclusive expression in microglia and/or are linked to immune function*. Ongoing work suggests many of these genes connect within important microglial molecular networks as ligand activators ( IL34 ), immune receptors ( TREM2, MS4A4A, HLA-DQA1 & CD33 ), signalling intermediates ( PLCG2 , PTK2B & INPP5D) or effector mechanisms (ABI3 & EPHA1 ). In some cases, evidence links them to specific core pathogenic immune responses and cell mechanisms such as complement (CR1 & CLU) or cytoskeletal machinery ( ABI3 , EPHA1 and FERMT2 ). However, more work is needed to establish whether these risk variants lead to gain or loss of protein function and to connect them to other genes within effector pathways and downstream cell processes which themselves could be tractable targets for treatment development. Brain tissue analysis and cell models of genetic risk carriers will help enormously to