Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease

Nat Commun. 2017 Apr 3:8:14727. doi: 10.1038/ncomms14727.

Abstract

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / physiopathology*
  • Animals
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Dendritic Spines / metabolism
  • Dihydroxyphenylalanine / pharmacology
  • Dihydroxyphenylalanine / therapeutic use
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology*
  • Food
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Inflammation / complications
  • Inflammation / pathology
  • Memory*
  • Mice, Transgenic
  • Nerve Degeneration / complications
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / pathology
  • Neuronal Plasticity / drug effects
  • Nucleus Accumbens / pathology
  • Nucleus Accumbens / physiopathology
  • Plaque, Amyloid / complications
  • Plaque, Amyloid / pathology
  • Plaque, Amyloid / physiopathology
  • Reward*
  • Selegiline / pharmacology
  • Selegiline / therapeutic use
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / pathology
  • Ventral Tegmental Area / physiopathology

Substances

  • Selegiline
  • Dihydroxyphenylalanine