MON-568 HMGA1 Deficiency Ties Insulin Resistance to Tau-Related Neurodegeneration

Abstract Disclosure: M. Mirabelli: None. F.S. Brunetti: None. E. Chiefari: None. D.P. Foti: None. A. Brunetti: None. Background: Growing evidence links tau-related neurodegeneration, a hallmark of Alzheimer's disease (AD) and other tauopathies, to insulin resistance (IR). However, the molecular mechanisms underlying this association remain unclear. The chromatin factor HMGA1, a key regulator of the insulin receptor and glucose metabolism genes, has been implicated in IR and diabetes when defective. A known genetic variant, HMGA1 rs146052672, disrupts HMGA1 protein production. This study investigates whether HMGA1 deficiency contributes to tauopathy development and its intersection with IR. Methods: We used human and mouse neuronal cell models to perform immunoblotting, protein-DNA interaction assays, chromatin immunoprecipitation, and reporter gene analyses. In Hmga1 knockout mice, we examined tau immunoreactivity, behavioral phenotypes, and brain glucose metabolism. We also conducted a case-control study involving 69 patients with AD or non-AD tauopathies and 200 age-matched controls to assess the clinical and molecular impact of the HMGA1 rs146052672 variant. Results: In vitro, HMGA1 bound to the tau promoter and repressed tau gene transcription. Reduced HMGA1 levels in neuronal cells and primary mouse neurons led to increased tau mRNA and protein, along with oxidative stress and reactive oxygen species (ROS) accumulation. In Hmga1 knockout mouse brains, we observed increased tau expression, hyperphosphorylation, and toxic tau aggregation, alongside reduced insulin receptor levels and impaired glucose uptake. These molecular and metabolic alterations were associated with behavioral deficits similar to those in classic tauopathy models and clinical features of human AD and non-AD tauopathies. In the case-control study, the HMGA1 rs146052672 variant was four times more prevalent in tauopathy patients than in controls. Carriers had significantly higher levels of total and phosphorylated tau in cerebrospinal fluid, faster disease progression, worse treatment outcomes, and more severe IR. Conclusion: These findings suggest that HMGA1 deficiency drives both IR and the pathological overproduction and aggregation of tau, establishing a mechanistic link between metabolic dysfunction and neurodegeneration. HMGA1 may thus represent a central player in the pathogenesis of both IR and tauopathy, making it a promising target for predicting and developing therapeutic strategies for these diseases. Presentation: Monday, July 14, 2025