Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models

Nat Med. 2019 Jan;25(1):165-175. doi: 10.1038/s41591-018-0275-4. Epub 2019 Jan 7.

Abstract

Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology*
  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Fibronectins / cerebrospinal fluid
  • Fibronectins / genetics
  • Fibronectins / metabolism*
  • Humans
  • Long-Term Potentiation
  • Male
  • Memory Disorders / complications*
  • Memory Disorders / physiopathology*
  • Mice, Inbred C57BL
  • Middle Aged
  • Neuronal Plasticity*
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Physical Conditioning, Animal*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Signal Transduction

Substances

  • FNDC5 protein, human
  • FNDC5 protein, mouse
  • Fibronectins
  • Neuroprotective Agents
  • RNA, Messenger
  • Recombinant Proteins