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.

Neuroinflammation is one of the hallmarks of Parkinson’s disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD – to modulate disease progression – still remain unexplored. Here we show that rats overexpressing human α-synuclein (Syn) display altered DA neuron properties, reduced striatal DA outflow and motor deficits prior to nigral degeneration. These early alterations are coupled with microglia activation and perturbations of inflammatory and pro-resolving mediators, namely IFN-γ and resolvin D1 (RvD1). Chronic and early RvD1 administration in Syn rats prevents central and peripheral inflammation, as well as neuronal dysfunction and motor deficits. We also show that endogenous RvD1 is decreased in human patients with early-PD. Our results suggest there is an imbalance between neuroinflammatory and pro-resolving processes in PD.

The ␤3 neuronal nicotinic subunit is localized in dopaminergic areas of the central nervous system, in which many other neuronal nicotinic subunits are expressed. So far, ␤3 has only been shown to form functional receptors when expressed together with the ␣3 and ␤4 subunits. We have systematically tested in Xenopus laevis oocytes the effects of coexpressing human ␤3 with every pairwise functional combination of neuronal nicotinic subunits likely to be relevant to the central nervous system. Expression of ␣7 homomers or ␣/␤ pairs (␣2, ␣3, ␣4, or ␣6 together with ␤2 or ␤4) produced robust nicotinic currents for all combinations, save ␣6␤2 and ␣6␤4. Coexpression of wild-type ␤3 led to a nearly complete loss of function (measured as maximum current response to acetylcholine) for ␣7 and for all functional ␣/␤ pairs except for ␣3␤4. This effect was also seen in hippocampal neurons in culture, which lost their robust ␣7-like responses when transfected with ␤3. The level of surface expression of nicotinic binding sites (␣3␤4, ␣4␤2, and ␣7) in tsA201 cells was only marginally affected by ␤3 expression. Furthermore, the dominant-negative effect of ␤3 was abolished by a valine-serine mutation in the 9Ј position of the second transmembrane domain of ␤3, a mutation believed to facilitate channel gating. Our results show that incorporation of ␤3 into neuronal nicotinic receptors other than ␣3␤4 has a powerful dominant-negative effect, probably due to impairment in gating. This raises the possibility of a novel regulatory role for the ␤3 subunit on neuronal nicotinic signaling in the central nervous system.