Elevated TMPRSS6 affects cognition and learning in Alzheimer’s disease through neuronal iron dysregulation

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Aim: TMPRSS6, a type II transmembrane serine protease predominantly expressed in the liver, plays a crucial role in regulating systemic iron homeostasis. However, the expression and function of TMPRSS6 in the central nervous system remain poorly understood. Methods: Adeno-associated viruses (AAVs) carrying plasmids with neuron-specific promoters for TMPRSS6 knockdown were stereotactically injected into the hippocampus of 6-month-old wild-type (WT) and amyloid precursor protein (APP)/PS1 male mice. Three months later, the mice underwent a water maze test, and hippocampal tissues were collected for subsequent experiments. Results: The analysis of Alzheimer’s disease (AD) databases we describe here identified a significant increase in TMPRSS6 mRNA levels in the hippocampus of AD patients, a finding corroborated by elevated TMPRSS6 expression in the hippocampus of APP/PS1 transgenic mice, which exhibit an AD phenotype. Knockdown of TMPRSS6 in the hippocampus of these mice led to a significant enhancement in cognitive and learning abilities, accompanied by a reduction in the accumulation of APP and amyloid-beta (Aβ) plaques. Further experiments revealed that TMPRSS6 knockdown decreased iron and reactive oxygen species (ROS) levels in the hippocampus, upregulated glutathione peroxidase 4 (GPX4), downregulated acyl-CoA synthetase long-chain family member 4 (ACSL4), ameliorated mitochondrial cristae damage, and inhibited ferroptosis, which might be associated with the bone morphogenic protein/Smad signaling pathway. Conclusion: Our findings shed light on the role of TMPRSS6 in the central nervous system, which may offer valuable insights for the development of therapeutic strategies for AD or other disorders associated with brain iron accumulation.