Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease.
Annalisa NobiliEmanuele Claudio LatagliataMaria Teresa ViscomiVirve CavallucciDebora CutuliGiacomo GiacovazzoParaskevi KrashiaFrancesca Romana RizzoRamona MarinoMauro FedericiPaola De BartoloDaniela AversaMaria Concetta Dell'AcquaAlberto CordellaMarco SancandiFlavio KellerLaura PetrosiniStefano Puglisi-AllegraNicola Biagio MercuriRoberto CoccurelloNicola BerrettaMarcello D'AmelioPublished in: Nature communications (2017)
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.
Keyphrases
- mouse model
- cell death
- prefrontal cortex
- spinal cord
- oxidative stress
- working memory
- coronary artery disease
- cognitive decline
- endothelial cells
- traumatic brain injury
- end stage renal disease
- newly diagnosed
- ejection fraction
- mass spectrometry
- patient reported outcomes
- risk assessment
- cell proliferation
- high resolution
- atomic force microscopy
- depressive symptoms
- deep brain stimulation
- mild cognitive impairment
- brain injury
- protein kinase
- sleep quality