Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer's disease

Cordella, Alberto; Krashia, Paraskevi; Nobili, Annalisa; Pignataro, Annabella; Barbera, Livia La; Viscomi, Maria Teresa; Valzania, Alessandro; Keller, Flavio; Ammassari–Teule, Martine; Mercuri, Nicola Biagio; Berretta, Nicola; D’Amelio, Marcello

doi:10.1016/j.nbd.2018.05.006

Cited by 54 publications

(58 citation statements)

References 80 publications

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“…2-3). These results are supported by recent results obtained on a validated mouse model of AD [32,33] and corroborated by previous post-mortem [2,[7][8][9][10][11] and in vivo imaging evidence [19,34], reporting pre-synaptic dopaminergic dysfunction in AD-D. We also provide a new remarkable nding of system-level dopaminergic alterations, with disruption of the pattern of regional connectivity observed in HC (Fig. 4).…”

Section: Discussionsupporting

confidence: 91%

In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

Perani

Sala

Caminiti

et al. 2021

Preprint

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Background Preclinical and pathology evidence suggest an involvement of brain dopamine (DA) circuitry in Alzheimer’s Disease (AD). We in vivo investigated, if, when and in which target regions, DA signaling and molecular connectivity are damaged along the AD course. Methods We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D) and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial-correlation analysis. Results were deemed significant at p<0.05, after Bonferroni correction for multiple comparisons. Results We found significant reductions of dopamine transporter density in both AD-MCI and AD-D compared to controls. Dopaminergic deficits were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced dopaminergic transporter density, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient < 0.25), and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). Conclusion Local and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

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Section: Discussionsupporting

confidence: 91%

In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

Perani

Sala

Caminiti

et al. 2021

Preprint

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“…The brains were removed and postfixed in paraformaldehyde at 4°C and then immersed in 30% sucrose solution at 4°C until sinking. The brains were then cut into 30-μm-thick coronal sections using a freezing microtome, to be used for immunohistochemistry and immunofluorescence 76,77 .…”

Section: Rotarod Testmentioning

confidence: 99%

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

et al. 2019

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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.

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“…Degeneration of VTA dopamine neurons in Tg2576 mice is evident as early as 3 months of age and is accompanied by significant levels of local inflammation, while cell death worsens with age (Nobili et al, 2017; D'Amelio and Nisticò, 2018). The degeneration of dopamine neurons results in lower dopamine outflow in the hippocampus and NAc and correlates temporally with impairments in hippocampal neuronal excitability, synaptic plasticity, memory, and reward performance (Nobili et al, 2017; Cordella et al, 2018). Other brain regions containing TH + neurons, in particular the Substantia Nigra pars compacta (SNpc) and Locus Coeruleus (LC), are intact in Tg2576 mice at least at early stages (Nobili et al, 2017), suggesting that the observed degeneration primarily affects the VTA.…”

mentioning

confidence: 99%

Unifying Hypothesis of Dopamine Neuron Loss in Neurodegenerative Diseases: Focusing on Alzheimer's Disease

Krashia

Nobili

D’Amelio

2019

Front. Mol. Neurosci.

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Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer's disease

Cited by 54 publications

References 80 publications

In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

Unifying Hypothesis of Dopamine Neuron Loss in Neurodegenerative Diseases: Focusing on Alzheimer's Disease

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