Visceral adipose tissue differentially affects tau and Aβ pathology in 3xTg-AD mice

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Abstract
Alzheimer's disease (AD) is a complex disorder involving multiple cellular and molecular mechanisms. Recent evidence suggests that metabolic alterations play a crucial role in AD progression. Likewise, diabetes and obesity-two major metabolic diseases-are well-established risk factors for AD. These conditions are associated with a significant expansion of white adipose tissue (WAT). Here, we hypothesize that visceral WAT may act as a key mediator between peripheral metabolic dysfunction and brain illnesses. Immunohistochemistry and biochemical approaches were used to evaluate the WAT from WT and db/db mice. Similar techniques were applied to examine the brain tissue of 3xTg-AD mice that received white epididymal fat pads from WT or db/db donors and determine the impact of adipose tissue transplantation on tau and Aβ pathology. Our study revealed that recipient 3xTg-AD mice that received db/db fat pads developed profound changes in tau pathology due to increased expression of the cyclin-dependent kinase 5 activator p25 compared with 3xTg-AD mice that received fad pads from WT or sham mice. This increment in p25/cdk5 was associated with a prominent inflammatory response induced by the WAT transplant. Moreover, the opposite effect on Aβ pathology was found. The reduction in Aβ levels was correlated with an increase in microglial phagocytic capacity. Overall, our study demonstrated a novel crosstalk between AD and metabolic disorders through white adipose signaling resulting in differential effects on tau and Aβ pathology mediated by an activated immune response.
Funding Information
  • University of Málaga, Spain (B1-2021_32)
  • Universidad de Málaga (961.662)
  • Instituto de Salud Carlos III (PI21/00915)
  • National Institutes of Health (U54-AG054349)
  • BrightFocus Foundation (A2015535S)
  • Ministerio de Ciencia e Innovación (PID2019-108911RA-100)
  • Alzheimer's Association (AARG-22-928219)
  • Ministerio de Ciencia e Innovación, programa Beatriz Galindo (BEAGAL18/00052)
  • IBIMA Plataforma BIONAND (INTAR25-11)

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