Exploration of the molecular neighbourhood of the α7 nicotinic acetylcholine receptor to understand its intracellular trafficking and its role in Alzheimer’s disease

Alzheimer’s disease (AD) is one of the major debilitating diseases for older individuals globally. It is characterised by progressive cognitive decline and aberrant protein aggregates in the brain. Although investigated for decades, the disease is still incurable. The cholinergic hypothesis is one of the earliest theories explaining AD and suggests that the loss of cholinergic synapse homeostasis is the primary event leading to AD-associated cognitive impairment. Neuronal α7 nicotinic acetylcholine receptor (α7 nAChR) is a crucial component of a cholinergic synapse, and its expression levels are reduced in the AD brain. Although many studies have shown the pivotal role of α7 nAChR in AD, little is known about the basic mechanisms governing receptor biogenesis and trafficking to the synapse where it exerts its function. Only recently have some of the α7 nAChR interactors essential for its surface expression been identified. Here, we propose a proximity labelling approach and a new cellular model to investigate α7 nAChR interactome. This is the first successful screen of potential α7 nAChR molecular partners, where we detected several known receptor interactors, and uncovered many proteins that have never been linked to the receptor before. We tested a selection of these proteins and discovered that some of them regulate α7 nAChR intracellular localisation. This opens doors to a better understanding of α7 nAChR cellular functions on many levels, including its role in autophagy, neuronal plasticity, and cellular mechanisms of memory - all of which are perturbed in multiple neurological disorders, including AD. Additionally, we explore an alternative theory of AD and the potential role of a T14 peptide in α7 nAChR-mediated neurotoxicity. Investigating α7 nAChR interactome could help answer some fundamental questions, such as why cholinergic signalling is primarily affected in AD, and how this translates into memory loss and cognitive impairment in AD.