Seipin knockdown ameliorates Alzheimer's cognitive deficits by reducing ferroptosis via glycine pathway

Despite significant research, Alzheimer's disease (AD) remains an incurable neurodegenerative disorder with complex pathogenesis. Emerging evidence highlights metabolic dysregulation and ferroptosis as critical contributors to neuronal loss in AD. While the BSCL2 gene, encoding Seipin, is known for its role in lipid metabolism, its specific involvement in AD progression and its link to ferroptosis have been unclear. Understanding this axis could reveal novel therapeutic targets beyond amyloid and tau pathologies, addressing a crucial gap in AD treatment strategies.

Researchers employed a multi-modal approach, including Mendelian randomization (MR) analysis, in vivo APP/PS1 mouse models, and in vitro BV2 microglial assays. For in vivo studies, stereotactic knockdown of Seipin was performed in the hippocampus of APP/PS1 mice. In vitro, Aβ-stimulated microglia were used to assess ferroptosis markers. Glycine supplementation was also tested to counteract Seipin overexpression-induced ferroptosis, investigating its role in glutathione synthesis. Primary endpoints included cognitive function, ferroptosis markers (GPX4, Nrf2, HO-1, ACSL4, NCOA4), and systemic metabolic toxicity.

MR analysis revealed a causal relationship between genetically predicted elevated BSCL2 expression and an increased risk of Alzheimer's disease, with glycine partially mediating this effect. Supporting these genetic insights, stereotactic knockdown of Seipin in the hippocampus of APP/PS1 mice significantly ameliorated cognitive deficits without inducing systemic metabolic toxicity. Mechanistically, Seipin deficiency consistently reduced ferroptosis in both AD mouse brains and Aβ-stimulated microglia. This reduction was evidenced by the upregulation of anti-ferroptotic markers like GPX4, Nrf2, and HO-1, alongside the suppression of pro-ferroptotic effectors such as ACSL4 and NCOA4. Glycine supplementation partially reversed the aggravated ferroptotic phenotype caused by Seipin overexpression, indicating a functional feedback loop where glycine facilitates glutathione synthesis to mitigate Seipin-induced lipid peroxidation. These findings collectively identify Seipin as a novel regulator of ferroptosis in AD pathogenesis.

Seipin deficiency significantly reduced ferroptosis in AD mouse brains and Aβ-stimulated microglia, upregulating anti-ferroptotic markers (GPX4, Nrf2, HO-1) and suppressing pro-ferroptotic effectors (ACSL4, NCOA4).