Prenatal stress promotes icv-STZ-induced sporadic Alzheimer's pathology through central insulin signaling change

Life Sci. 2020 Jan 15;241:117154. doi: 10.1016/j.lfs.2019.117154. Epub 2019 Dec 16.


Aim: Insulin resistance and neuroinflammation play roles in Alzheimer's (AD) etiology. Insulin receptors (IR) are developmentally expressed in neurons as well as astrocytes. Moreover, prolonged stress can induce brain insulin resistance and astrogliosis. Also, prenatal stress could advance AD-related abnormalities in a transgenic model of AD. Besides, postnatal maternal care (PMC) has antagonistic effects on prenatal stress (PS)-induced neuronal and immunological malfunctions. Using an icv-STZ subclinical model of sAD, we assessed PS and/or abnormal PMC impacts on advancing sAD-like pathology in adult male rats. We also sought astrocyte- and/or neuron-oriented change in central insulin programming.

Main methods: Pregnant rats were exposed to PS. Thereafter, a group of pups was fostered onto unstressed mothers and the others remained intact. Real-time RT-PCR- for hippocampal IR, Tau, and ChAT transcripts- and immunohistochemistry analysis- for GFAP+ astrocytes- were performed at the first- and forth-postnatal-week, respectively. The other animals received icv-STZ0.5 mg/kg in adulthood and subjected to cognitive tests, molecular, and histological experiments at appropriate time-point post-injection.

Key findings: PS could advance sAD-related symptoms in icv-STZ-treated animals. PS changed expression levels of hippocampal IR in one-week-old and 5.5-month-old offspring. PS could worsen cognitive, molecular and histological impairments of icv-STZ. Adequate PMC prevented some destructive effects of PS.

Significance: PS can potentially change central insulin programming and induce long-lasting astrogliosis in rat hippocampus. PS-related cognitive and histological pathologies can rescue by PMC probably via IR-dependent pathways. Astrocyte involvement in AD-like neuropathology observed in stressed-animals needs more detailed investigations.

Keywords: Icv-STZ; Insulin resistance; Perinatal stress; Programming; Rat; sAD.

MeSH terms

  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Animals
  • Animals, Newborn
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / toxicity
  • Behavior, Animal*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal*
  • Female
  • Infusions, Intraventricular
  • Insulin Resistance*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / physiopathology*
  • Rats
  • Rats, Wistar
  • Receptor, Insulin / metabolism
  • Signal Transduction
  • Streptozocin / administration & dosage
  • Streptozocin / toxicity*
  • Stress, Psychological / complications*


  • Antibiotics, Antineoplastic
  • Streptozocin
  • Receptor, Insulin