Work

Increased type 3 deiodinase reduces hippocampal T3 signaling and is associated with cognitive impairment in a sporadic Alzheimer’s disease animal model

Year: 2026

Type: article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β and tau pathology, neuroinflammation, oxidative stress, and cognitive decline. Emerging evidence indicates that thyroid hormone (TH) dysregulation may also contribute to AD pathogenesis, particularly through impaired hippocampal signaling. THs are crucial for neuronal metabolism, plasticity, and mitochondrial integrity, and their local availability is tightly controlled by deiodinases. This study investigated the role of type 3 deiodinase (D3) and its redox-dependent regulation via glutathione (GSH) in a streptozotocin (STZ)-induced model of sporadic AD. Male Wistar rats received intracerebroventricular STZ or vehicle and were evaluated 16 weeks later. STZ-treated rats exhibited significant deficits in short-term (p = 0.0090) and long-term (p = 0.0117) memory, accompanied by elevated hippocampal IL-6 and TNF-α (p < 0.0001), increased protein carbonylation (p = 0.0162), and depletion of GSH (p = 0.0326) and sulfhydryl groups (p = 0.0165). D3 mRNA (p < 0.0001) and protein (p = 0.0247) were upregulated, while T3-responsive genes Klf9 (p < 0.0001) and HR (p = 0.0353) were downregulated, indicating impaired TH signaling. Mitochondrial dysfunction was evidenced by reduced expression of Nrf1 (p = 0.0337), PGC-1α (p = 0.0035), Bcl2 (p = 0.0305), and COX4 (p = 0.0077), with increased CHOP (p = 0.0034), GRP78 (p < 0.0001), and ERK activation (p < 0.0001).Together, these findings demonstrate that inflammation- and redox-driven D3 upregulation decreases hippocampal T3 availability, disrupting TH signaling and promoting mitochondrial dysfunction and cognitive decline in sporadic AD.

Source: Scientific Reports

DOI: 10.1038/s41598-026-43232-1

Authors: Rafael Aguiar Marschner, Rafael Teixeira Ribeiro, Vitor Gayger-Dias, Vanessa-Fernanda Da Silva, Simone Magagnin Wajner, Carlos-Alberto Gonçalves

Institutions: Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,690