A Novel Peptide Driving Neurodegeneration Appears Exclusively Linked to the α7 Nicotinic Acetylcholine Receptor.

Sanskar Ranglani, Sibah Hasan, Joanna Komorowska, Nathalia Mayag Medina, Kashif Mahfooz, Anna Ashton, Sara Garcia-Ratés, Susan Greenfield

Molecular neurobiology 2024 Oct

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T14, a 14mer peptide, is significantly increased in the pre-symptomatic Alzheimer's disease brain, and growing evidence implies its pivotal role in neurodegeneration. Here, we explore the subsequent intracellular events following binding of T14 to its target α7 nicotinic acetylcholine receptor (nAChR). Specifically, we test how various experimental manipulations of PC12 cells impact T14-induced functional outcomes. Three preparations were compared: (i) undifferentiated vs. NGF-differentiated cells; (ii) cells transfected with an overexpression of the target α7 nAChR vs. wild type cells; (iii) cells transfected with a mutant α7 nAChR containing a mutation in the G protein-binding cluster, vs. cells transfected with an overexpression of the target α7 nAChR, in three functional assays - calcium influx, cell viability, and acetylcholinesterase release. NGF-differentiated PC12 cells were less sensitive than undifferentiated cells to the concentration-dependent T14 treatment, in all the functional assays performed. The overexpression of α7 nAChR in PC12 cells promoted enhanced calcium influx when compared with the wild type PC12 cells. The α7345-348 A mutation effectively abolished the T14-triggered responses across all the readouts observed. The close relationship between T14 and the α7 nAChR was further evidenced in the more physiological preparation of ex vivo rat brain, where T30 increased α7 nAChR mRNA, and finally in human brain post-mortem, where levels of T14 and α7 nAChR exhibited a strong correlation, reflecting the progression of neurodegeneration. Taken together these data would make it hard to account for T14 binding to any other receptor, and thus interception at this binding site would make a very attractive and remarkably specific therapeutic strategy. © 2024. The Author(s).

Citation

Sanskar Ranglani, Sibah Hasan, Joanna Komorowska, Nathalia Mayag Medina, Kashif Mahfooz, Anna Ashton, Sara Garcia-Ratés, Susan Greenfield. A Novel Peptide Driving Neurodegeneration Appears Exclusively Linked to the α7 Nicotinic Acetylcholine Receptor. Molecular neurobiology. 2024 Oct;61(10):8206-8218