1. Academic Validation
  2. Aβ initiates brain hypometabolism, network dysfunction and behavioral abnormalities via NOX2-induced oxidative stress in mice

Aβ initiates brain hypometabolism, network dysfunction and behavioral abnormalities via NOX2-induced oxidative stress in mice

  • Commun Biol. 2021 Sep 9;4(1):1054. doi: 10.1038/s42003-021-02551-x.
Anton Malkov  # 1 Irina Popova  # 1 Anton Ivanov 2 Sung-Soo Jang 3 Seo Yeon Yoon 3 Alexander Osypov 1 4 Yadong Huang 3 5 Yuri Zilberter  # 2 Misha Zilberter  # 6
Affiliations

Affiliations

  • 1 Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.
  • 2 Aix Marseille Université, Inserm, Marseille, France.
  • 3 Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
  • 4 Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia.
  • 5 Department of Neurology, University of California, San Francisco, CA, USA.
  • 6 Gladstone Institute of Neurological Disease, San Francisco, CA, USA. [email protected].
  • # Contributed equally.
Abstract

A predominant trigger and driver of sporadic Alzheimer's disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH Oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18950
    99.71%, NOX2 Inhibitor