The effect of hyperthyroidism on cognitive function, neuroinflammation, and necroptosis in APP/PS1 mice

Background Increasing evidence has linked the thyroid dysfunction to the pathogenesis of dementia. Evidence from clinical studies has demonstrated that hypothyroidism is related to an increased risk of dementia. But the association of hyperthyroidism with dementia is largely unknown. Methods We used the adenovirus containing thyrotropin receptor (TSHR) amino acid residues 1-289 (Ad-TSHR289)-induced Graves' disease (GD) phenotype in Alzheimer's disease (AD) model mice (APP/PS1 mice) to evaluate the effect of hyperthyroidism on the cognitive function and [beta]-amyloid (A[beta]) accumulation. Results GD mice exhibited a stable long-term hyperthyroidism and cognitive deficits. Single Cell RNA-sequencing analysis indicated that microglia function played a critical role in the pathophysiological processes in GD mice. Neuroinflammation and polarization of microglia (M1/M2 phenotype) and activated receptor-interacting serine/threonine protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudo-kinase (MLKL)-mediated necroptosis contributed to the pathological process, including A[beta] deposition and neuronal loss. RIPK3 inhibitor could inhibit GD-mediated A[beta] accumulation and neuronal loss. Conclusions Our findings reveal that GD hyperthyroidism aggravates cognitive deficits in AD mice and induces A[beta] deposition and neuronal loss by inducing neuroinflammation and RIPK3/MLKL-mediated necroptosis. Keywords: Alzheimer's disease, Graves' disease, Single cell RNA-sequencing, Neuroinflammation, Necroptosis