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.
Highlights
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
Midbrain DAergic neurons project to the striatum and nucleus accumbens (NAc) topographically along the mediolateral axis: the shell subregion of the NAc is innervated by medially located ventral tegmental area (VTA) neurons mediating motivation, reward-related cognition and multiple forms of memory; the NAc core is innervated by lateral VTA and medial substantia nigra pars compacta (SNpc) neurons influencing motor responses related to a Number of neurons of VTA Number of neurons of SNpc b
In a mouse model of AD, at a stage when no Ab-plaque deposition, hyperphosphorylated tau tangles or any sign of neuronal loss in cortical and hippocampal regions involved in memory deficits has yet occurred[21,23,24], we provide evidence that a specific apoptotic process is taking place in the VTA, causing a progressive degeneration of the DAergic neuronal population
Summary
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. Pioneering neuropathological observations in post-mortem AD brain[12,13] demonstrated that the hippocampal formation and extrinsic (both cortical and sub-cortical) connections are disrupted at multiple levels, suggesting that the progressive structural alterations in the different brain areas may contribute to the worsening of memory and cognitive functions in AD patients. Consistent with these observations, several alterations in the dopaminergic (DAergic) system have been reported in AD patients, including reduced levels of dopamine (DA) and its receptors[14,15,16]. VTA DAergic neurons target the nucleus accumbens (NAc) and cerebral cortex, mediating the control of incentive motivation and reward processing[17]
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