Circulating Agonist Autoantibody to 5-Hydroxytryptamine 2A Receptor in Lean and Diabetic Fatty Zucker Rat Strains

M B Zimering1,2, M Grinberg1, J Burton1

  • 1Medical Service, Veterans Affairs New Jersey Healthcare System, East Orange, New Jersey, USA.

Endocrinology, Diabetes and Metabolism Journal
|October 14, 2020
PubMed
Abstract

Insights

Neurotoxic autoantibodies targeting the 5-hydroxytryptamine 2A receptor increase in aging male Zucker diabetic fatty rats. These autoantibodies are linked to neurodegeneration and are present in specific Zucker rat strains, suggesting a role for immunity in late-stage neurodegeneration.

Area of Science:

  • Neuroscience
  • Immunology
  • Endocrinology

Background:

  • Type 2 diabetes is associated with neurodegenerative complications in older adults.
  • Neurotoxic autoantibodies targeting the 5-hydroxytryptamine 2A receptor (5-HT2AR) have been implicated in these complications.
  • The male Zucker diabetic fatty (ZDF) rat serves as a model for obese type 2 diabetes.

Purpose of the Study:

  • To investigate and compare circulating neurotoxic autoantibodies against 5-HT2AR in ZDF rats and age-matched lean Zucker rats.
  • To determine the developmental profile and persistence of these autoantibodies.

Main Methods:

  • Plasma from lean and ZDF rats at various developmental stages was used.
  • Immunoglobulin G (IgG) fractions were isolated via protein G affinity chromatography.
  • Neurotoxicity was assessed using N2A mouse neuroblastoma cells, measuring neurite retraction and neuron loss.
  • Binding to a synthetic peptide of the 5-HT2AR second extracellular loop was evaluated.

Main Results:

  • Autoantibodies to 5-HT2AR were spontaneously detected in male ZDF rats (fa/fa) and Zucker lean rats (fa/+) around 7-8.5 weeks of age, persisting until at least 25 weeks in ZDF and fa/+ rats.
  • These autoantibodies were absent in 25-week-old lean Zucker rats (+/?).
  • Autoantibody-induced neurotoxicity in N2A cells was dose-dependently inhibited by 5-HT2AR antagonists and signaling pathway inhibitors (RhoA/ROCK, Gq11/PLC/IP3R).

Conclusions:

  • Neurotoxic 5-HT2AR autoantibodies increase in aging male ZDF rats and heterozygous Zucker lean rats, but not in age-matched lean rats without the leptin receptor mutation.
  • The Zucker rat strain is a valuable model for studying the role of humoral and innate immunity in late-onset neurodegeneration.

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