2',3'-Dideoxycytidine, a DNA Polymerase-β Inhibitor, Reverses Memory Deficits in a Mouse Model of Alzheimer's Disease

J Alzheimers Dis. 2019;67(2):515-525. doi: 10.3233/JAD-180798.

Abstract

The etiology and pathogenesis of Alzheimer's disease (AD) are not fully understood. Thus, there are no drugs available that can provide a cure for it. We and others found that DNA polymerase-β (DNA pol-β) is required for neuronal death in several neurodegenerative models. In the present study, we tested the effect of a DNA pol-β inhibitor 2',3'- Dideoxycytidine (DDC) in AD models both in vitro and in vivo. DDC protected primary neurons from amyloid-β (Aβ)-induced toxicity by inhibiting aberrant DNA replication mediated by DNA pol- β. Chronic oral administration of DDC alleviated Aβ deposition and memory deficits in the Tg2576 mouse model of AD. Moreover, DDC reversed synaptic loss in Tg2576 mice. These results suggest that DDC represents a novel therapeutic agent for the treatment of AD.

Keywords: 2′,3′– Dideoxycytidine; Alzheimer’s disease; DNA polymerase-β; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / psychology
  • Amyloid beta-Peptides / toxicity
  • Animals
  • DNA Polymerase beta / antagonists & inhibitors*
  • DNA Polymerase beta / metabolism
  • DNA Replication / drug effects
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / therapeutic use*
  • Maze Learning / drug effects
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Memory Disorders / psychology
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neuroprotective Agents / adverse effects
  • Neuroprotective Agents / therapeutic use*
  • Primary Cell Culture
  • Synapses / drug effects
  • Synapses / pathology
  • Zalcitabine / adverse effects
  • Zalcitabine / therapeutic use*

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Zalcitabine
  • DNA Polymerase beta