GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease

Nat Med. 2014 Aug;20(8):886-96. doi: 10.1038/nm.3639. Epub 2014 Jun 29.

Abstract

In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Bestrophins
  • Cerebellum / metabolism
  • Dentate Gyrus / metabolism
  • Disease Models, Animal
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • GABA Antagonists / therapeutic use
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Male
  • Maze Learning
  • Memory / drug effects
  • Memory Disorders / drug therapy
  • Memory Disorders / etiology
  • Memory Disorders / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Monoamine Oxidase / genetics
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / pharmacology
  • Peptide Fragments / pharmacology
  • Plaque, Amyloid / metabolism
  • Putrescine / pharmacology
  • RNA, Small Interfering / genetics
  • Receptors, GABA / metabolism
  • gamma-Aminobutyric Acid / biosynthesis*

Substances

  • Amyloid beta-Peptides
  • Best1 protein, mouse
  • Bestrophins
  • Eye Proteins
  • GABA Antagonists
  • Ion Channels
  • Monoamine Oxidase Inhibitors
  • Peptide Fragments
  • RNA, Small Interfering
  • Receptors, GABA
  • amyloid beta-protein (1-42)
  • gamma-Aminobutyric Acid
  • Monoamine Oxidase
  • Amyloid Precursor Protein Secretases
  • Putrescine