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

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer'sdisease (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 ofAD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we foundan age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaquestages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. Theselective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampusand nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates withimpairments in CA1 synaptic plasticity, memory performance and food reward processing.We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons atpre-plaque stages contributes to memory deficits and dysfunction of reward processing