biostudies-literatureMirabelli MGoverno Italiano Ministero dell&apos;Istruzione dell&apos;Universita e della RicercaMinistero della SaluteMinistero dell’Istruzione, dell’Università e della RicercaUniversity College London105700https://www.ebi.ac.uk/biostudies/studies/S-EPMC12019291biostudies-literatureUnknown115<h4>Background</h4>Growing evidence links tau-related neurodegeneration with insulin resistance and type 2 diabetes (T2D), though the underlying mechanisms remain unclear. Our previous research identified HMGA1 as crucial for insulin receptor (INSR) expression, with defects in the HMGA1 gene associated with insulin resistance and T2D. Here, we explore HMGA1 deficiency as a potential contributor to tauopathies, such as Alzheimer's disease (AD), and its connection to insulin resistance.<h4>Methods</h4>Immunoblot analyses, protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays were conducted in human and mouse neuronal cell models. Tau immunohistochemistry, behavioural studies, and brain glucose metabolism were analysed in Hmga1-knockout mice. Additionally, a case-control study EBioMedicineHMGA1 deficiency: a pathogenic link between tau pathology and insulin resistance.PMC12019291202279JKW5WFR PNRR-MCNT2-2023-12377884MUR-PRIN 2022Di Vito AGreco AFedele MChiefari EBrunetti FSNicoletti FPierantoni GMArcidiacono BHuin VPascarella AAguglia USalatino ACredendino SCMirabelli MMorelli MFoti DPBrunetti AfalseHMGA1 deficiency: a pathogenic link between tau pathology and insulin resistance.<h4>Background</h4>Growing evidence links tau-related neurodegeneration with insulin resistance and type 2 diabetes (T2D), though the underlying mechanisms remain unclear. Our previous research identified HMGA1 as crucial for insulin receptor (INSR) expression, with defects in the HMGA1 gene associated with insulin resistance and T2D. Here, we explore HMGA1 deficiency as a potential contributor to tauopathies, such as Alzheimer's disease (AD), and its connection to insulin resistance.<h4>Methods</h4>Immunoblot analyses, protein-DNA interaction studies, ChIP-qPCR, and reporter gene assays were conducted in human and mouse neuronal cell models. Tau immunohistochemistry, behavioural studies, and brain glucose metabolism were analysed in Hmga1-knockout mice. Additionally, a case-control study 2025-01-01T00:00:00Z2025 May2026-07-15T08:52:30.633Z2025-07-12T03:04:03.155ZS-EPMC120192914023365910.1016/j.ebiom.2025.105700