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Fingolimod alleviates type 2 diabetes associated cognitive decline by regulating autophagy and neuronal apoptosis via

Jie Li1, Mingjie Yin1, Zhen Wang2

  • 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang 050000, China.

Brain Research
|September 16, 2024
PubMed

Insights

Fingolimod (FTY720) improves cognitive function and reduces hippocampal damage in type 2 diabetes mice by enhancing autophagy and inhibiting apoptosis via the AMPK/mTOR pathway, without altering blood glucose levels.

Area of Science:

  • Neuroscience
  • Endocrinology
  • Pharmacology

Background:

  • Type 2 diabetes mellitus is associated with cognitive decline.
  • Fingolimod (FTY720) is an immunomodulator with potential neuroprotective properties.
  • The role of FTY720 in diabetes-associated cognitive dysfunction requires further investigation.

Purpose of the Study:

  • To investigate the effect of fingolimod (FTY720) on cognitive decline in a mouse model of type 2 diabetes.
  • To explore the underlying neuroprotective mechanisms of FTY720, focusing on autophagy, apoptosis, and the AMPK/mTOR signaling pathway.

Main Methods:

  • Type 2 diabetes was induced in mice using a high-fat diet and streptozotocin.
  • Mice were treated with different doses of FTY720 for 8 weeks.
  • Cognitive function was assessed using Morris water maze and new object recognition tests.
  • Hippocampal tissues were analyzed for pathological changes, protein expression (autophagy, apoptosis, AMPK/mTOR pathway), and neuronal ultrastructure.

Main Results:

  • FTY720 treatment significantly improved cognitive function and reduced hippocampal damage in type 2 diabetic mice.
  • FTY720 modulated the expression of autophagy-related proteins (increased LC3 II/I ratio, Beclin-1; decreased P62) and apoptosis-related proteins (decreased Bax, increased Bcl-2).
  • FTY720 influenced the AMPK/mTOR signaling pathway and did not affect body weight or fasting blood glucose levels.

Conclusions:

  • Fingolimod (FTY720) demonstrates significant neuroprotective effects in type 2 diabetes-associated cognitive decline.
  • FTY720 enhances hippocampal autophagy and inhibits apoptosis, likely mediated through the AMPK/mTOR signaling pathway.
  • FTY720 represents a potential therapeutic agent for cognitive impairment in type 2 diabetes, independent of glycemic control.
Keywords:
ApoptosisAutophagyCognitive impairmentFTY720Type 2 diabetes

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