RT journal article
T1 Diabetes-linked metabolic dysfunction relates with distinct tau phosphorylation patterns, neuroinflammation and cognitive impairment in mouse models of Alzheimer's disease
A1 Vargas Soria, María
A1 Corraliza Gómez,  Miriam
A1 Infante-Garcia, Carmen
A1 Stitt, Alan W.
A1 Simó, Rafael
A1 García Alloza, Mónica
A2 BiomedicinaBiotecnología y Salud Pública
K1 Alzheimer’s disease
K1 Cognitive impairment
K1 Machine learning
K1 Prediabetes
K1 Tau phosphorylation
K1 Type 1 diabetes
K1 Type 2 diabetes
AB Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques and tau neurofibrillary tangles, with tau pathology being closely linked to cognitive decline. Growing evidence suggests that metabolic dysfunction including type 1 diabetes (T1D) and type 2 diabetes (T2D), as well as prediabetes (PreDM), exacerbate AD by promoting different degrees of insulinopenia, insulin resistance and hyperglycemia which can drive chronic inflammation and oxidative stress across multiple organs. Precisely how these metabolic disturbances influence tau phosphorylation remains unclear. To address this, we studied mouse models of AD, T1D, PreDM, T2D and the combination of AD with all three metabolic alterations, at 26 weeks of age, when pathologies are well established. The fact that we are including models of insulin resistance and insulin deficiency allows us to further explore the specific role of insulin as observed in the clinic. We assessed metabolic status, tau phosphorylation and cytokine levels in the brain cortex and cognitive function using the Morris water maze (MWM) and novel object discrimination (NOD) tests. Our results revealed that AD mice with metabolic disorders exhibited tau hyperphosphorylation, particularly at Ser199, Ser202/Thr205 and Ser404, correlating with metabolic dysfunction, cognitive impairment and inflammatory markers. Notably, AD-T2D mice showed the most severe deficits in MWM and NOD performance, indicating a synergistic cognitive decline. Machine learning analysis by random forest effectively classified AD-metabolic phenotypes, identifying key molecular and metabolic markers of neurodegeneration, mainly blood glucose and plasma insulin. These findings highlight the critical role of metabolic dysfunction in exacerbating tau pathology and accelerating cognitive decline in AD. Targeting metabolic pathways may provide concomitant therapeutic opportunities for AD patients with diabetes. Future research should explore interventions that restore insulin signaling and glucose metabolism to mitigate AD progression, probably by repurposing antidiabetic drugs.
PB Elsevier
SN 1090-2139
YR 2025
FD 2025-11-30
LK http://hdl.handle.net/10498/38842
UL http://hdl.handle.net/10498/38842
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 15-nov-2026