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

Annalisa Nobili(Università Campus Bio-Medico), Emanuele Claudio Latagliata(Fondazione Santa Lucia), Maria Teresa Viscomi(Fondazione Santa Lucia), Virve Cavallucci(Università Cattolica del Sacro Cuore), Debora Cutuli(Fondazione Santa Lucia), Giacomo Giacovazzo(Fondazione Santa Lucia), Paraskevi Krashia(University of Rome Tor Vergata), Francesca Romana Rizzo(University of Rome Tor Vergata), Ramona Marino(Università Campus Bio-Medico), Mauro Federici(Fondazione Santa Lucia), Paola De Bartolo(Marconi University), Daniela Aversa(University of Rome Tor Vergata), Maria Concetta Dell’Acqua(Università Campus Bio-Medico), Alberto Cordella(University of Rome Tor Vergata), Marco Sancandi(Sapienza University of Rome), Flavio Keller(Università Campus Bio-Medico), Laura Petrosini(Fondazione Santa Lucia), Stefano Puglisi‐Allegra(Fondazione Santa Lucia), Nicola Biagio Mercuri(University of Rome Tor Vergata), Roberto Coccurello(Fondazione Santa Lucia), Nicola Berretta(Fondazione Santa Lucia), Marcello D’Amelio(Università Campus Bio-Medico)
Nature Communications
April 3, 2017
10.1038/ncomms14727
Cited by 503Open Access
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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.

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