P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer's disease model

J Exp Med. 2018 Jun 4;215(6):1649-1663. doi: 10.1084/jem.20171487. Epub 2018 May 3.

Abstract

Astrocytic hyperactivity is an important contributor to neuronal-glial network dysfunction in Alzheimer's disease (AD). We have previously shown that astrocyte hyperactivity is mediated by signaling through the P2Y1 purinoreceptor (P2Y1R) pathway. Using the APPPS1 mouse model of AD, we here find that chronic intracerebroventricular infusion of P2Y1R inhibitors normalizes astroglial and neuronal network dysfunction, as measured by in vivo two-photon microscopy, augments structural synaptic integrity, and preserves hippocampal long-term potentiation. These effects occur independently from β-amyloid metabolism or plaque burden but are associated with a higher morphological complexity of periplaque reactive astrocytes, as well as reduced dystrophic neurite burden and greater plaque compaction. Importantly, APPPS1 mice chronically treated with P2Y1R antagonists, as well as APPPS1 mice carrying an astrocyte-specific genetic deletion (Ip3r2-/-) of signaling pathways downstream of P2Y1R activation, are protected from the decline of spatial learning and memory. In summary, our study establishes the restoration of network homoeostasis by P2Y1R inhibition as a novel treatment target in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / analogs & derivatives
  • Adenosine Diphosphate / pharmacology
  • Adenosine Diphosphate / therapeutic use
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cognition* / drug effects
  • Disease Models, Animal
  • Hippocampus / pathology
  • Humans
  • Memory / drug effects
  • Mice, Transgenic
  • Nerve Net / drug effects
  • Nerve Net / physiopathology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Plaque, Amyloid / metabolism
  • Purinergic P2Y Receptor Antagonists / pharmacology
  • Purinergic P2Y Receptor Antagonists / therapeutic use*
  • Receptors, Purinergic P2Y1 / metabolism*
  • Signal Transduction / drug effects
  • Synapses / drug effects
  • Synapses / metabolism

Substances

  • N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y1
  • Adenosine Diphosphate