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

Nobili, Annalisa; Latagliata, Emanuele Claudio; Viscomi, Maria Teresa; Cavallucci, Virve; Cutuli, Debora; Giacovazzo, Giacomo; Krashia, Paraskevi; Rizzo, Francesca Romana; Marino, Ramona; Federici, Mauro; De Bartolo, Paola; Aversa, Daniela; Dell’Acqua, Maria Concetta; Cordella, Alberto; Sancandi, Marco; Keller, Flavio; Petrosini, Laura; Puglisi-Allegra, Stefano; Mercuri, Nicola Biagio; Coccurello, Roberto; Berretta, Nicola; D’Amelio, Marcello

doi:10.1038/ncomms14727

Cited by 521Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

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

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Nobili, Annalisa, Latagliata, Emanuele Claudio, Viscomi, Maria Teresa, Cavallucci, Virve, Cutuli, Debora, Giacovazzo, Giacomo, Krashia, Paraskevi, Rizzo, Francesca Romana +14 more·2017·Nature Communications

DOI 10.1038/ncomms14727PMC PMC5382255

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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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TL;DR

In the Tg2576 mouse model of Alzheimer’s disease, selective apoptotic loss of ventral tegmental area (VTA) dopaminergic neurons begins at 3 months of age, before amyloid plaques, while substantia nigra pars compacta neurons remain intact. This VTA degeneration is associated with reduced dopamine outflow in the hippocampus and nucleus accumbens shell, impaired CA1 synaptic plasticity, memory deficits, and altered food reward processing, which are rescued by L-DOPA or selegiline.

Key findings

Tg2576 mice showed significant loss of tyrosine hydroxylase-positive (TH+) dopaminergic neurons in the VTA beginning at 3 months of age, with no loss in the SNpc at any age tested; TH− cell numbers remained constant, indicating true neuronal loss rather than only TH downregulation.
At 6 months, evoked dopamine release was significantly decreased in the NAc shell but not in the NAc core or dorsal striatum; microdialysis also showed reduced basal dopamine in the hippocampus and NAc shell, while noradrenaline outflow in the hippocampus did not differ between genotypes.
CA3-to-CA1 LTP was normal at 2 months but significantly lower in 6-month-old Tg2576 mice; contextual fear-conditioning memory deficits and chocolate-conditioned place preference/food consumption deficits were absent at 2 months and present at 6 months.
Sub-chronic L-DOPA (10 mg kg−1 plus 12 mg kg−1 benserazide) or selegiline (3 mg kg−1) rescued LTP, restored hippocampal PSD composition and spine density, improved contextual fear memory and Morris water maze spatial memory, and restored food reward processing in 6-month-old Tg2576 mice.

Methods

Male heterozygous Tg2576 mice and wild-type littermates, ages 2–11 months, were used; experiments followed European ethical guidelines and Italian Health Ministry approval.
The study combined stereological counts of TH+ and TH− neurons in VTA, SNpc, and locus coeruleus; TUNEL, GFAP, Iba1, DAT, and APPswe immunohistochemistry/immunofluorescence; microdialysis; amperometry in acute slices; multielectrode array electrophysiology; PSD fractionation and immunoblotting; Golgi-Cox spine analysis; and behavioral tests including conditioned place preference, contextual fear conditioning, and Morris water maze.
Statistical analyses used two-way or one-way ANOVAs with Tukey’s or Bonferroni’s post hoc tests, repeated-measures ANOVAs for microdialysis, and two-tailed paired or unpaired Student’s t-tests for other data; significance was set at P≤0.05.

Limitations

Stated: the authors cannot exclude reduced axonal dopamine release from locus coeruleus TH+ neurons, especially in older animals; cannot exclude other Aβ aggregation forms in VTA neurons; and cannot exclude that selegiline’s rescue of behavioral deficits might involve additional brain regions.
Stated: selegiline’s effectiveness in human patients is controversial, and its effectiveness could depend on the degree of VTA neurodegeneration.
Evident: the study is limited to male Tg2576 mice, a single transgenic AD model, and the link between VTA dopaminergic loss and behavioral/synaptic deficits is largely correlational plus pharmacological rescue rather than causal cell-specific manipulation.

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Crossref · 10.1038/ncomms14727

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Findingown data
GFAP immunoreactivity is unchanged in the SNpc of 3-month-old Tg2576 mice.
“Instead, GFAP immunoreactivity was unchanged in the SNpc of 3-month-old Tg2576 mice, in line with the observation that nigral DAergic neurons are intact (Fig. 2b).”
Quote in the paperNot a substantial claim
Findingown data
Extracellular Aβ-plaque deposition is absent in 6-month-old Tg2576 mice in the midbrain dopaminergic neurons and in projection areas including hippocampus, dorsal striatum and NAc.
“We found that extracellular Aβ-plaque deposition was absent in 6-month-old mice in all of the above-mentioned regions.”
Quote in the paperSubstantial claim
Findingown data
In 2-month-old Tg2576 mice, DA release in the NAc shell is similar between genotypes.
“In addition, in 2-month-old mice, when the number of DAergic neurons in the Tg2576 VTA is still unchanged compared to WT animals, the release of DA in the NAc shell is similar between genotypes (Supplementary Fig. 2a).”
Quote in the paperSubstantial claim
Findingown data
In Tg2576 mice, cytoplasmic APPswe staining is more intense in the hippocampus and NAc shell than in other areas.
“However, we observed more intense cytoplasmic staining for APPswe in the hippocampus and NAc shell of Tg2576 mice compared to the other areas (Supplementary Fig. 1a).”
Quote in the paperNot a substantial claim
Findingown data
There is a significant increase in GFAP+ cells in the VTA of 3-month-old Tg2576 mice, indicating increased reactive astrocytes in response to dopaminergic neuronal loss.
“Consistent with greater neuronal degeneration27, we found a significant rise in the number of GFAP+ cells in the VTA of 3-month-old Tg2576 mice, demonstrating an increase in reactive astrocytes in response to DAergic neuronal loss.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [27] Middeldorp, J. & Hol, E. M. GFAP in health and disease. Prog. Neurobiol. 93, 421–443 (2011). source
  Not checked in the free run.

Findingown data
Tg2576 mice consume less chocolate during the conditioning phase of the CPP task.
“In addition, Tg2576 mice consumed less chocolate during the conditioning phase (Fig. 3g).”
Quote in the paperSubstantial claim
Findingown data
In the VTA of 3-month-old Tg2576 mice, there are more shrunken-appearing and TUNEL-positive apoptotic cells.
“In agreement with the selective loss of VTA DAergic neurons, we detected more shrunken appearance and TUNEL-positive apoptotic cells in the VTA of 3-month-old Tg2576 mice, the age at which the TH+ cell number starts to decline (Fig. 2a).”
Quote in the paperSubstantial claim
Findingown data
Microdialysis confirms reduced outflow of DA in the NAc shell of 6-month-old Tg2576 mice.
“Microdialysis experiments performed on freely moving animals confirmed the reduced outflow of DA in the NAc shell of 6-month-old Tg2576 mice (Fig. 3d).”
Quote in the paperSubstantial claim
Findingown data
In vivo microdialysis detects significantly reduced basal DA levels in the striatum of 6-month-old Tg2576 mice.
“Surprisingly, in vivo microdialysis detected significantly reduced levels of basal DA also in the striatum (Fig. 3e).”
Quote in the paperSubstantial claim
Findingown data
In a chocolate-elicited conditioned place preference task, Tg2576 mice fail to develop preference for the chocolate-paired chamber.
“In contrast, place conditioning was absent in Tg2576 mice: these animals spent equal amounts of time in the chocolate-paired chamber during the pre-conditioning and testing session and failed to develop any preference for the chamber with the rewarding food (Fig. 3f).”
Quote in the paperSubstantial claim
Findingown data
In Tg2576 mice, there is an age-dependent loss of TH+ dopaminergic neurons in the ventral tegmental area (VTA) beginning at 3 months of age.
“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.”
- Also stated in: § DAergic neuron degeneration in the VTA at pre-plaque stages · plain
  “We observed a significant loss of DAergic neurons in Tg2576 mice, beginning at 3 months of age (Fig. 1b).”
Quote in the paperSubstantial claim
Findingown data
In 2-month-old Tg2576 mice, LTP in CA3-to-CA1 synapses does not differ significantly from age-matched controls.
“In 2-month-old animals, when DAergic neuron numbers in the VTA are still intact, LTP in Tg2576 animals did not differ significantly from age-matched controls (Supplementary Fig. 3a).”
Quote in the paperSubstantial claim
Findingown data
LTP magnitude is significantly lower in 6-month-old Tg2576 mice.
“Instead, LTP magnitude was significantly lower in 6-month-old Tg2576 mice (Fig. 4h), an age at which VTA DAergic cell death is pronounced and DA outflow in the hippocampus is significantly reduced.”
Quote in the paperSubstantial claim
Findingown data
L-DOPA treatment rescues LTP deficits in Tg2576 mice by restoring LTP to WT levels.
“On the other hand, L-DOPA treatment rescued LTP deficits in Tg2576 mice by restoring LTP to the levels of WT animals (Fig. 5a).”
Quote in the paperSubstantial claim
Findingown data
Selegiline improves spatial memory of Tg2576 mice, as indicated by increased distance travelled in the target quadrant during the Probe phase of the Morris water maze.
“Furthermore, selegiline improved spatial memory of Tg2576 mice, as indicated by the increased distance travelled in the target quadrant that previously contained the escape platform during the Probe phase of a Morris water maze test (Fig. 7c, Supplementary Fig. 5d–f).”
Quote in the paperSubstantial claim
Findingown data
Selegiline treatment rescues LTP magnitude in 6-month-old Tg2576 mice without affecting WT animals.
“Similarly to L-DOPA, selegiline treatment rescued the LTP magnitude in 6-month-old Tg2576 mice, without affecting WT animals (Fig. 5b).”
Quote in the paperSubstantial claim
Findingown data
Selegiline fails to rescue TH levels in 6-month-old Tg2576 mice.
“As expected, selegiline failed to rescue TH levels in 6-month-old Tg2576 mice (Fig. 6a, Supplementary Fig. 7a).”
Quote in the paperSubstantial claim
Findingown data
Sub-chronic selegiline treatment increases DA outflow in the hippocampus of Tg2576 mice.
“Microdialysis experiments on freely moving animals confirmed that sub-chronic treatment with selegiline increased DA outflow in the hippocampus of Tg2576 mice (Supplementary Fig. 4d).”
Quote in the paperSubstantial claim
Findingown data
Noradrenaline outflow in the hippocampus does not differ between Tg2576 and WT mice at 6 months.
“On the other hand, noradrenaline outflow in the hippocampus did not differ between genotypes (Fig. 4b), suggesting that at this age the noradrenergic projection from the LC is preserved.”
Quote in the paperSubstantial claim
Findingown data
TH protein levels in the striatum of Tg2576 mice are identical to WT mice.
“Instead, TH protein levels of Tg2576 were identical to WT animals in the striatum (Fig. 4g, Supplementary Fig. 6b), in accordance with amperometric data in this area and the observation that SNpc DAergic neurons, mainly projecting to the striatum, are still intact at this age.”
Quote in the paperSubstantial claim
Findingown data
Surface expression of the AMPAR GluA1 subunit is down-regulated in the hippocampal PSD fraction of 6-month-old Tg2576 mice.
“Consistent with our previous observations in 3-month-old animals25, the surface expression of the AMPAR GluA1 subunit was down-regulated in 6-month-old Tg2576 mice (Fig. 4i, Supplementary Figs 3d,e and 6c).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [25] D’Amelio, M. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat. Neurosci. 14, 69–76 (2011). source
  Not checked in the free run.
Findingown data
There are no differences in other post-synaptic components, including D2 receptors, in the hippocampal PSD of Tg2576 mice.
“We did not observe differences in other post-synaptic components, including D2 receptors (Fig. 4i).”
Quote in the paperNot a substantial claim
Findingown data
L-DOPA sub-chronic treatment leads to restoration of both D1 receptors and GluA1 expression in hippocampal PSD fractions.
“Similar results were also obtained by L-DOPA sub-chronic treatment that led to a restoration of both D1 receptors and GluA1 expression in hippocampal PSD fractions (Fig. 6c, Supplementary Fig. 7c).”
Quote in the paperSubstantial claim
Findingown data
Activation of D1 receptors is followed by an increase of GluA1 expression in the PSD.
“The activation of D1 receptors was followed by the increase of GluA1 expression in the PSD (Fig. 6b), in line with previous reports5556.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [5556]
  Not checked in the free run.
Findingcitation
Memory deficits are absent in 2-month-old Tg2576 mice.
“Importantly, as previously reported2325, memory deficits were absent in 2-month-old Tg2576 mice (Supplementary Fig. 3g), in line with the absence of DAergic cell death in the VTA before 3 months of age.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [2325]
  Not checked in the free run.
Findingown data
The number of TH+ neurons in the LC does not differ between Tg2576 and WT mice at 6 months.
“LC stereological cell-count confirmed that, at this age, the number of TH+ neurons in this brain region did not differ between genotypes (Fig. 4c,d).”
Quote in the paperSubstantial claim
Findingown data
Microdialysis indicates reduced DA outflow in the hippocampus of 6-month-old Tg2576 mice compared to age-matched controls.
“However, microdialysis experiments on freely moving animals indicated a reduced DA outflow in the hippocampus of 6-month-old Tg2576 mice compared to age-matched controls (Fig. 4a).”
Quote in the paperSubstantial claim
Findingown data
The loss of VTA DAergic neurons is paralleled by reduced outflow of DA in the hippocampus and in the shell region of the NAc.
“The loss of VTA DAergic neurons is paralleled by a reduced outflow of DA in the hippocampus and in the shell region of the NAc.”
Quote in the paperSubstantial claim
Findingown data
Both selegiline and L-DOPA treatments increase total freezing time elicited by re-exposure to aversive stimuli during a CFC task in 6-month-old Tg2576 mice.
“Indeed, both selegiline (Supplementary Fig. 5a) and L-DOPA (Supplementary Fig. 4a) treatments increased the total freezing time elicited by re-exposure to aversive stimuli during a CFC task in 6-month-old Tg2576 mice (Fig. 7a,b, Supplementary Fig. 5b,c).”
Quote in the paperSubstantial claim
Findingown data
Selegiline triggers removal of D1 receptors from the PSD in both WT and Tg2576 mice.
“This activity appeared to depend on the effects of selegiline on D1 exposure because it triggered the removal of D1 receptors from the PSD in both WT and Tg2576 mice (Fig. 6b, Supplementary Fig. 7b), likely as compensatory response to DA availability.”
Quote in the paperSubstantial claim
Findingown data
No abnormal pattern in the distribution of APPswe immunofluorescence suggests a link between intracellular Aβ and cell degeneration.
“Although we cannot exclude the accumulation of other Aβ aggregation forms in VTA neurons, we did not observe any abnormal pattern in the distribution of APPswe immunofluorescence that could suggest a link between intracellular Aβ and cell degeneration.”
Quote in the paperSubstantial claim
Findingown data
In a contextual fear-conditioning task, total freezing time after re-exposure to an aversive context declines in 6-month-old Tg2576 mice.
“During CFC, the total freezing time after re-exposure to an aversive context declined in 6-month-old Tg2576 mice (Fig. 4j, Supplementary Fig. 3f).”
Quote in the paperSubstantial claim
Findingown data
L-DOPA treatment causes a slight, non-significant increase in CA3-to-CA1 LTP magnitude in 6-month-old WT mice compared to saline controls.
“Six-month-old WT animals sub-chronically treated with L-DOPA had a slight, yet not significant increase in the magnitude of CA3-to-CA1 LTP compared to saline-treated (sham) controls (Fig. 5a).”
Quote in the paperNot a substantial claim
Findingown data
Selegiline treatment restores the defects in CPP and food consumption observed in Tg2576 mice.
“As expected, although saline-treated Tg2576 animals were unable to show increased preference for the chamber associated with the rewarding food and consumed less chocolate during the conditioning phase, these deficits were absent from selegiline-treated mice (Fig. 7d,e).”
Quote in the paperSubstantial claim
Findingown data
Recovery of hippocampal CA3-to-CA1 synaptic plasticity and PSD composition by selegiline correlates with restoration of spine density in pyramidal neuron apical dendrites in the CA1 stratum radiatum.
“The recovery of the hippocampal CA3-to-CA1 synaptic plasticity and PSD composition in Tg2576 mice by selegiline was also correlated with the restoration of spine density in pyramidal neuron apical dendrites located in the CA1 stratum radiatum (Fig. 6d,e).”
Quote in the paperSubstantial claim
Interpretationown data
The decrease in TH+ cells in the VTA of Tg2576 mice reflects a true loss of dopaminergic neurons rather than loss of TH immunoreactivity or down-regulation of TH expression.
“In contrast with TH+ cells, the number of TH− cells remained constant (Fig. 1b), indicating that the decrease of TH+ cells in the VTA of Tg2576 mice reflects a true loss of DAergic neurons and not a mere loss of TH immunoreactivity or down-regulation of TH expression.”
Quote in the paperSubstantial claim
Interpretationreasoning
The reduced basal DA levels in the striatum of Tg2576 mice likely reflect alterations in the control of tonic DA release.
“Considering that both the SNpc DAergic neurons (Fig. 1b) and striatal DA release by phasic DAergic activity (Fig. 3b) were intact in Tg2576 mice, it is likely that the reduced basal levels of DA in the striatum might reflect alterations in the control of tonic DA release3637.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [3637]
  Not checked in the free run.
Premiseown data
Activation of D1 receptors increases GluA1 expression in the PSD.
“The activation of D1 receptors was followed by the increase of GluA1 expression in the PSD (Fig. 6b), in line with previous reports5556.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [5556]
  Not checked in the free run.
Interpretationown data
In the Tg2576 mouse model, a specific apoptotic process in the VTA causes progressive degeneration of the DAergic neuronal population.
“Here, in a mouse model of AD, at a stage when no Aβ-plaque deposition, hyperphosphorylated tau tangles or any sign of neuronal loss in cortical and hippocampal regions involved in memory deficits has yet occurred212324, we provide evidence that a specific apoptotic process is taking place in the VTA, causing a progressive degeneration of the DAergic neuronal population.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites 212324
  Not checked in the free run.
Interpretationown data
The VTA is an important area of the brain to consider in the context of AD.
“Although the molecular mechanisms underlying early VTA DAergic neuron degeneration remain to be elucidated, our results suggest the VTA as an important area of the brain to consider in the context of AD.”
Quote in the paperNot a substantial claim
Interpretationown data
The progression of memory and synaptic deficits in Tg2576 mice follows the onset of VTA neuronal degeneration at 3 months of age.
“We found that the progression of these deficits in the Tg2576 mouse model follows the onset of VTA neuronal degeneration at 3 months of age.”
Quote in the paperSubstantial claim
Interpretationown data
Increased availability of DA in the hippocampus and NAc can ameliorate mnesic deficits and impairment in mesolimbic reward processing in 6-month-old Tg2576 mice.
“We conclude that the increased availability of DA in the hippocampus and NAc can ameliorate mnesic deficits and impairment in mesolimbic reward processing in 6-month-old Tg2576 mice.”
Quote in the paperSubstantial claim

May combine two claims. 26
Classified as probably not a substantial claim. 23

May combine two claims.
Findingown data
In 2-month-old Tg2576 mice, there is no impairment in place preference or food consumption.
“In 2-month-old Tg2576 mice, when the outflow of DA in the NAc shell is still normal, there is no impairment in place preference or food consumption (Supplementary Fig. 2d,e).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Extracellular Aβ-plaque deposition is detected in the hippocampus of 11-month-old Tg2576 mice, but not in the VTA.
“Extracellular Aβ-plaque deposition was detected in the hippocampus of aging (11-month-old) Tg2576 mice, but not in the VTA (Supplementary Fig. 1c).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
In 3-month-old Tg2576 mice, microglial morphology changes and the ratio of mildly activated to resting microglia increases in the VTA, while microglia in the SNpc remain unchanged.
“In agreement with DAergic cell loss in the VTA, in 3-month-old Tg2576 animals we observed a change in microglial morphology and a significant increase in the ratio of mildly activated over resting cells, whereas microglia in the SNpc area remained unchanged (Fig. 2c).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
The loss of TH+ dopaminergic neurons in Tg2576 mice is restricted to the VTA; SNpc dopaminergic neurons are intact at all ages tested.
“This reduction in TH+ cell number was restricted to the VTA, as no difference was observed between Tg2576 and WT mice in the SNpc at any age tested (Fig. 1b).”
- Also stated in: § Abstract · plain
  “although substantia nigra pars compacta (SNpc) DAergic neurons were intact.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
In 6-month-old Tg2576 mice, evoked DA release is significantly decreased in the NAc shell, but not in the NAc core or dorsal striatum.
“In 6-month-old Tg2576 mice, when the DAergic neuronal loss in the VTA reaches a plateau (Fig. 1a), the evoked DA was significantly decreased in the NAc shell (Fig. 3b). Instead, no difference was observed in the NAc core or in the striatum (Fig. 3b).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
DAT staining is reduced in the NAc shell, but not in the NAc core, of 6-month-old Tg2576 mice.
“Consistent with the amperometric results, staining for the DA transporter (DAT), used as a specific marker of DAergic terminals, was reduced in the NAc shell, but not in the NAc core of 6-month-old Tg2576 mice (Fig. 3c).”
Quote in the paperSubstantial claim
May combine two claims.
Findingreasoning
Hippocampal synaptic plasticity, PSD composition, pyramidal neuron spine density, mnesic performances and reward processing are all improved by stimulating the DA system with L-DOPA or selegiline.
“Accordingly, hippocampal synaptic plasticity and PSD composition, pyramidal neuron spine density, mnesic performances and reward processing, are all improved by stimulating the DA system with administration of L-DOPA or with reduction of endogenous DA degradation with selegiline.”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
Selegiline-induced increase in DA availability restores GluA1 phosphorylation (Ser845) levels in Tg2576 mice while having no effect in controls.
“However, the selegiline-induced increase in DA availability restored GluA1 phosphorylation (Ser845) levels in Tg2576 mice while having no effect in controls (Fig. 6a).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
The input-output relationship is similar between WT and Tg2576 mice, indicating no change in basal synaptic transmission.
“The input–output relationship was also similar between WT and Tg2576 mice, indicating no change in basal synaptic transmission (Supplementary Fig. 3c).”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
The rescue effect of L-DOPA on LTP in Tg2576 mice is reproduced by acute bath application of L-DOPA and mimicked by the D1/D5 receptor agonist SKF38393.
“The rescue effect of L-DOPA in Tg2576 mice was reproduced by acute, bath-application of L-DOPA (10 μM) during LTP recordings and it was mimicked by the selective D1/D5 receptor agonist SKF38393 (10 μM; Supplementary Fig. 4b).”
Quote in the paperSubstantial claim
May combine two claims.
Findingcitation
DA outflow to the NAc core and DAT levels are unchanged in Tg2576 mice.
“Curiously, DA outflow to the NAc core (and DAT levels) was unchanged in Tg2576 mice, even though this region is heavily innervated by VTA DAergic neurons34.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [34] Lammel, S. et al. Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57, 760–773 (2008). source
  Not checked in the free run.
May combine two claims.
Findingown data
TH protein levels and TH immunoreactivity in the hippocampus are significantly reduced in 6-month-old Tg2576 mice.
“In line with these data, we found that both the TH protein levels (Fig. 4e, Supplementary Fig. 6a) and TH immunoreactivity (Fig. 4f) in the hippocampus were significantly reduced in 6-month-old Tg2576 mice.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
The apoptotic cell death observed in VTA DAergic neurons as early as 3 months occurs at hippocampal pre-plaque stages and does not appear to result from local Aβ-plaque deposition in the VTA.
“These data indicate that the apoptotic cell death observed in VTA DAergic neurons as early as 3 months occurs at hippocampal pre-plaque stages in this animal model and does not appear to result from local Aβ-plaque deposition in the VTA.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
DAergic neurons show diffuse intracellular staining that is similar in the VTA and SNpc, suggesting the absence of intracellular Aβ accumulation in VTA neurons that could account for selective cell degeneration.
“Importantly, DAergic neurons showed diffuse intracellular staining, and this was similar in the VTA and SNpc, suggesting the absence of intracellular Aβ accumulation in VTA neurons that could account for the selective cell degeneration (Supplementary Fig. 1a).”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Peak height obtained by oxidation of DA and noradrenaline was compared with that produced by a standard.
“Peak height obtained by oxidation of DA and noradrenaline was compared with that produced by a standard.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
VTA dopaminergic neurons target the nucleus accumbens and cerebral cortex, mediating control of incentive motivation and reward processing.
“VTA DAergic neurons also target the nucleus accumbens (NAc) and cerebral cortex, mediating the control of incentive motivation and reward processing17.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [17] Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013). source
  Not checked in the free run.
May combine two claims.
Interpretationown data
Both exogenous (L-DOPA) and endogenous (selegiline)-induced increases in DA availability improve hippocampal plasticity, supporting the hypothesis that reduced DA outflow in the AD hippocampus worsens synaptic dysfunctions in Tg2576 mice.
“Thus, both exogenously (L-DOPA) and endogenously (selegiline)-induced increases in DA availability improved hippocampal plasticity, supporting our hypothesis that the reduced DA outflow in the AD hippocampus worsens synaptic dysfunctions in Tg2576 mice.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Study design and conductnone given
The correct positioning of microdialysis probes was confirmed under a microscope.
“The correct positioning of the probes was confirmed under a microscope.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Microdialysis membranes were tested for in vitro recovery before surgery.
“Membranes were tested for in vitro recovery before surgery.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
For CPP, animals were counterbalanced across groups.
“For CPP, animals were also counterbalanced across groups.”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
LC TH+ neurons can co-release DA together with noradrenaline, and the majority of TH+ projections in the hippocampus originate from the LC.
“Considering that LC TH+ neurons can also co-release DA together with noradrenaline4041 and that the majority of TH+ projections in the hippocampus originate from the LC4142, we performed a stereological cell-count of TH+ neurons in the LC of 6-month-old Tg2576 mice.”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [4041]
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- cites [4142]
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Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Data collection for cell counting was done by a researcher blind to the genotype of each animal.
“Data collection for cell counting was done by a researcher blind to the genotype of each animal.”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
Tg2576 transgenic mice overexpress human APP695 with the Swedish mutation (APPswe) and show behavioural and histopathological abnormalities that closely mimic early AD.
“Tg2576 transgenic mice overexpressing the human APP695 protein with the ‘Swedish' mutation (APPswe), which show behavioural and histopathological abnormalities that closely mimic early AD21.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [21] Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996). source
  Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown data
Unbiased estimates of total TH+ and TH− neurons in SNpc and VTA and TH+ neurons in LC were obtained using an optical fractionator stereological design.
“Sections processed for immunohistochemistry were used for obtaining unbiased estimates of total number of TH+ and TH− neurons in the SNpc and VTA and TH+ neurons in the LC.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
Hippocampal levels of D1 receptors increase significantly in the PSD of Tg2576 mice, suggesting a compensatory response to low basal DA.
“Conversely, we found that the hippocampal levels of D1 receptors increased significantly in the PSD of Tg2576 mice, suggesting the development of a compensatory response to low levels of basal DA.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
The early neuronal apoptotic cell death observed in VTA DAergic neurons occurs at hippocampal pre-plaque stages in the animal model and does not appear to result from local Aβ-plaque deposition in the VTA.
“In fact, we provide evidence that the early neuronal apoptotic cell death observed in VTA DAergic neurons occurs at hippocampal pre-plaque stages in our animal model, and does not appear to result from local Aβ-plaque deposition in the VTA.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Study design and conductnone given
In the contextual fear-conditioning test, the total duration of freezing during training and context test was manually scored by an observer blind to the experimental group of the specimen.
“the total duration of freezing (behavioural immobility, except for respiration movements) exhibited during training and context test was manually scored by an observer blind to the experimental group of the specimen”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationreasoning
The reduced DA outflow in the hippocampus of 6-month-old Tg2576 mice is principally due to VTA DAergic neuron degeneration, although reduced axonal DA release from LC TH+ neurons cannot be excluded.
“These data suggest that the reduced DA outflow in the hippocampus of 6-month-old Tg2576 mice is principally due to the established VTA DAergic neuron degeneration, although reduced axonal DA release from LC TH+ neurons cannot be excluded, especially in older animals4344.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [4344]
  Not checked in the free run.
May combine two claims.
Premisecitation
Dopamine modulates hippocampal synaptic plasticity, and its binding to dopaminergic receptors in the dorsal hippocampus is a major determinant of memory encoding.
“DA is a well-recognized modulator of hippocampal synaptic plasticity and its binding to DAergic receptors in the dorsal hippocampus is a major determinant of memory encoding181920.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites 181920
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
In the place conditioning task, for each genotype group, pairings were counterbalanced so that in half of the group chocolate was paired with one pattern and in the other half with the other pattern.
“For each genotype group pairings were counterbalanced so that in half of the group chocolate was paired with one of the patterns and in the other half with the other.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Dialysate concentrations were not corrected for probe recovery.
“Concentrations (pg 20 μl−1) were not corrected for probe recovery.”
Quote in the paperNot a substantial claim
Classified as probably not a substantial claim.
Premisecitation
PSD modifications precede functional alterations of synapses.
“As PSD modifications precede functional alterations of synapses25, we analysed protein expression in the hippocampal PSD fraction in 6-month-old Tg2576 mice.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [25] D’Amelio, M. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat. Neurosci. 14, 69–76 (2011). source
  Not checked in the free run.
May combine two claims.
Interpretationreasoning
Early degeneration of VTA DAergic neurons could account for the worsening of memory and for at least part of the non-cognitive symptoms reported in early AD patients.
“Thus, it is possible that early degeneration of VTA DAergic neurons could account for the worsening of memory as well as for at least part of the non-cognitive symptoms reported in early AD patients.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Premisecitation
One source of dopamine in the hippocampus derives from dopaminergic neurons in the VTA.
“One of the sources of DA in the hippocampus derives from DAergic neurons in the VTA17.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [17] Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat. Rev. Neurosci. 14, 609–625 (2013). source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Data collection for densitometry was done by a researcher blind to the genotype of each animal.
“Data collection for densitometry was done by a researcher blind to the genotype of each animal.”
Quote in the paperNot a substantial claim
Classified as probably not a substantial claim. May combine two claims.
Premisecitation
The NAc shell is innervated by medially located VTA neurons mediating motivation, reward-related cognition and multiple forms of memory; the NAc core is innervated by lateral VTA and medial SNpc neurons influencing motor responses related to reward stimuli; the dorsal striatum is almost exclusively innervated by laterally located SNpc neurons controlling voluntary movement.
“Midbrain DAergic neurons project to the striatum and NAc topographically along the mediolateral axis: the shell subregion of the NAc is innervated by medially located VTA neurons mediating motivation, reward-related cognition and multiple forms of memory; the NAc core is innervated by lateral VTA and medial SNpc neurons influencing motor responses related to reward stimuli, whereas the dorsal stri”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites 323435
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Data from animals not showing proper probe placement were discarded.
“Data from animals not showing proper placement were discarded.”
Quote in the paperNot a substantial claim
Classified as probably not a substantial claim.
Study design and conductown data
The specificity of immunohistochemical labelling was confirmed by omission of primary antibodies and use of normal serum as negative controls.
“The specificity of the immunohistochemical labelling was confirmed by the omission of primary antibodies and the use of normal serum instead (negative controls).”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
In the place conditioning task, the lighting conditions (visual and tactile cues) were adjusted to prevent preference for a certain chamber.
“The lighting conditions (visual and tactile cues) were adjusted to prevent preference for a certain chamber.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone given
The number of samples in each group for immunohistochemical, immunofluorescent, stereological, microdialysis, electrophysiological, biochemical, behavioural and morphological evaluations was determined based on published studies.
“The number of samples in each group for immunohistochemical, immunofluorescent, stereological, microdialysis, electrophysiological, biochemical, behavioural and morphological evaluations were determined based on published studies.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Animals used in all experiments were selected randomly.
“Animals used in all experiments were selected randomly.”
Quote in the paperNot a substantial claim
May combine two claims.
Interpretationown data
In Tg2576 mice, potentiation at CA3-to-CA1 synapses deteriorates with age and this impairment appears to follow the advancement of VTA DAergic cell death.
“Thus, in Tg2576 mice potentiation at CA3-to-CA1 synapses deteriorates with age and this impairment appears to follow the advancement of VTA DAergic cell death.”
Quote in the paperSubstantial claim
May combine two claims.
Interpretationown data
The reduced DA outflow in the Tg2576 hippocampus and NAc shell might largely contribute to deficits of hippocampus-dependent memory and synaptic plasticity, as well as impairment in reward processing.
“The reduced DA outflow in the Tg2576 hippocampus and NAc shell, brain areas primarily implicated in memory and reward, respectively, might largely contribute to the deficits of hippocampus-dependent memory and synaptic plasticity, as well as impairment in reward processing.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Study design and conductnone given
In the place conditioning task, the regular chow pellet and the chocolate portion provided each day were designed to be isocaloric.
“The RC pellet and the chocolate portion provided each day were designed to be isocaloric.”
Quote in the paperSubstantial claim
Classified as probably not a substantial claim.
Premisecitation
Alterations of the dopaminergic system, including reduced levels of dopamine and its receptors, have been reported in Alzheimer's disease 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 receptors141516.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites 141516
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
During morphological analysis of dendritic spines, the specimen identity was unknown to the analyst.
“During morphological analysis (Neurolucida v11, MicroBrightField) the specimen identity was unknown.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
In the place conditioning task, animals were randomly assigned to consume either chocolate or control diet.
“Animals were randomly assigned to consume either chocolate or control diet.”
Quote in the paperNot a substantial claim

47 of 47

The paper relies on this without support.
The cause of dopaminergic system dysfunction in Alzheimer's disease remains to be elucidated.
“However, the cause of DAergic system dysfunction in AD remains to be elucidated.”

1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

There is an early, progressive, and selective loss of VTA DA neurons in the Tg2576 mouse model of familial AD, long before Aβ plaque deposition.
“we have recently reported an early, pro gressive, and selective loss of the Ventral Tegmental Area (VTA) DA neurons in the Tg2576 mouse model of familiar AD, long before A β plaque deposition”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
Loss of TH+ terminals in the dorsal hippocampus and NAc shell results in a prominent drop of DA outflow to these projection areas and in a deficit of synaptic plasticity, followed by impairments in memory and reward performance in 6-month-old Tg2576 mice.
“Loss of tyrosine hydroxylase positive (TH + ) terminals in the dorsal hippocam pus and NAc shell results in a prominent drop of DA outflow to these projection areas and in a deficit of synaptic plasticity, followed by im pairments in memory and reward performance in 6-month-old Tg2576 mice (Cordella et al., 2018; Nobili et al., 2017).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
In the Tg2576 mouse model, degeneration of DA neurons results in lower DA outflow to projection areas including hippocampus and NAc shell, and correlates with impairment of the VTA-hippocampus-NAc circuit and with deficits in memory and reward performances.
“In the Tg2576 mouse model, the degeneration of DA neurons results in a lower DA outflow to the projection areas, including the hippocampus and NAc shell, and correlates with the impairment of the VTA-hippocampus-NAc circuit and with deficits in memory and reward performances”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
Degeneration of VTA DA neurons in the Tg2576 mouse model of AD is detectable since the age of 3 months and worsens over time.
“Degeneration of VTA DA neurons in the Tg2576 mouse model of AD is detectable since the age of 3 months, and it worsens over time.”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
At the age-point studied, no Aβ-plaque were detected in Tg2576 mice, as previously demonstrated.
“at an age-point when no A β -plaque were detected, as previously demon strated (Nobili et al., 2017).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017

The overall ~40% reduction of DA neurons in 6-month-old Tg2576 mice is the result of degeneration in more than one single subregion.
“In fact, stereological counting showed a trend towards DA neuron reduction in the lateral subfield of the VTA, although this result was not significant, suggesting that the overall ~40 % reduction of DA neurons in 6-month-old Tg2576 mice (Nobili et al., 2017) is the result of degeneration in more than one single subregion (see also Fig. 6B).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
All these deficits could be rescued by systemic treatment with the DA precursor levodopa.
“All these deficits could be rescued by systemic treatment with the DA precursor levodopa (Cordella et al., 2018; Nobili et al., 2017).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
Multiple functional alterations in Tg2576 DA neurons contribute to cell vulnerability and eventually lead to progressive degeneration and overt cognitive and non-cognitive deficits in older animals.
“The present data confirm the hypothesis that multiple functional alterations in Tg2576 DA neurons contribute to cell vulnerability and eventually lead to progressive degeneration and overt cognitive and non-cognitive deficits in older animals (Cordella et al., 2018; Nobili et al., 2017).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
Cognitive impairments in the Tg2576 model, at least until 6 months of age, are not related to dysfunctions in other DA-releasing neurons such as those in the locus coeruleus, given that this nucleus still appears to be intact and the levels of noradrenaline in the hippocampus are normal.
“On the other hand, we are fairly confident that cognitive impairments in our Tg2576 model, at least until 6 months of age, are not related to dysfunctions in other DA-releasing neurons such as those in the locus coeruleus, given that this nucleus still appears to be intact and the levels of noradrenaline in the hippocampus are normal (Nobili et al., 2017).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
This reduction in DA levels was associated with deficits in pyramidal neuron excitability and synaptic plasticity, and with dysfunctional hippocampal-related memory performance in Tg2576 mice.
“We had previously demonstrated that this reduction in DA levels was associated with deficits in pyramidal neuron excitability and synaptic plasticity, and with dysfunctional hippocam pal- related memory performance in Tg2576 mice.”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
VTA degeneration in Tg2576 mice results in lower DA innervation in the dorsal hippocampus, leading to lower DA outflow.
“VTA degeneration in Tg2576 mice results in lower DA innervation in the dorsal hippocampus, leading to lower DA outflow (Cordella et al., 2018; Nobili et al., 2017).”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017
These deficits temporally coincide with the onset of neuronal degeneration at 3 months.
“These deficits temporally coincide with the onset of neuronal degeneration (3 months; Nobili et al., 2017), and worsen with age.”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Nobili et al., 2017

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The substantia nigra and ventral tegmental area in Alzheimer’s disease and Down’s syndrome
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Opposing Roles of Nucleus Accumbens Core and Shell Dopamine in the Modulation of Limbic Information Processing
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A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease
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Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer’s disease
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Activation of D1/D5 Dopamine Receptors Protects Neurons from Synapse Dysfunction Induced by Amyloid-β Oligomers
Jürgensen, S., Antonio, L. L., Mussi, G. E. A., Brito-Moreira, J., Bomfim, T. R., De Felice, F. G., Garrido-Sanabria, E. R., Cavalheiro, É. A., & Ferreira, S. T. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.177790 · Cited by 88 · see citing works
Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25–35)
Tsunekawa, H., Noda, Y., Mouri, A., Yoneda, F., & Nabeshima, T. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.03.002 · Cited by 86 · see citing works
Dopaminergic neurotransmission dysfunction induced by amyloid-β transforms cortical long-term potentiation into long-term depression and produces memory impairment
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Early locus coeruleus degeneration and olfactory dysfunctions in Tg2576 mice
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Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia
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Decreased striatal D2 receptor density associated with severe behavioral abnormality in Alzheimer’s disease
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Actions of norepinephrine in the rat hippocampus
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On the properties of identified dopaminergic neurons in the mouse substantia nigra and ventral tegmental area
Krashia, P., Martini, A., Nobili, A., Aversa, D., D'Amelio, M., Berretta, N., Guatteo, E., & Mercuri, N. B. (2017) · European Journal of Neuroscience · doi:10.1111/ejn.13364 · Cited by 61 · see citing works
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Dopamine D2 receptors in the hippocampus and amygdala in Alzheimer's disease.
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The effect of selegiline in the treatment of people with Alzheimer's disease: a meta‐analysis of published trials
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L-Stepholidine rescues memory deficit and synaptic plasticity in models of Alzheimer’s disease via activating dopamine D1 receptor/PKA signaling pathway
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Selegiline in the treatment of mild to moderate Alzheimer-type dementia.
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Altered dopamine modulation of LTD-like plasticity in Alzheimer’s disease patients
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Monoamine Oxidase Inhibition Causes a Long-Term Prolongation of the Dopamine-Induced Responses in Rat Midbrain Dopaminergic Cells
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Dopamine agonists rescue Aβ–induced LTP impairment by Src-family tyrosine kinases
Yuanxiang, P., Janc, O. A., Grochowska, K. M., Kreutz, M. R., & Reymann, K. G. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.01.008 · Cited by 35 · see citing works
Pathway-Specific Alteration of Synaptic Plasticity in Tg2576 Mice
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Comparison of the effects of serotonin in the hippocampus and the entorhinal cortex
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Selegiline Reverses Aβ25–35-Induced Cognitive Deficit in Male Mice
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Learning deferred imitation of long spatial sequences
Drever, J., Straube, A. M., & Eggert, T. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.01.027 · Cited by 5 · see citing works

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Paxinos, G. & Franklin, K. The Mouse Brain in Stereotaxic Coordinates 4th edn Elsevier/Academic Press (2012).

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Microglia-mediated neuroinflammation in neurodegenerative diseases
Subhramanyam, C. S., Wang, C., Hu, Q., & Dheen, S. T. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.004 · Cited by 875 · see citing works
Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration
Kempuraj, D., Thangavel, R., Selvakumar, G. P., Zaheer, S. A., Ahmed, M. E., Raikwar, S. P., Zahoor, H., Saeed, D., Natteru, P., Iyer, S. S., et al. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00216 · Cited by 365 · see citing works
“DOPAMINE IN NEUROINFLAMMATION Neurotransmitter dopamine is implicated in the pathogenesis of PD and in AD (Bisaglia et al., 2014; Nobili et al., 2017).”
Background
Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation
Wang, C., Chen, S., Guo, H., Jiang, H., Liu, H., Fu, H., & Wang, D. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.69714 · Cited by 334 · see citing works
“In the Tg2576 mouse model of AD, age-dependent alterations in dopaminergic neuron loss in the ventral tegmental area occur prior to the formation of amyloid plaques, leading to memory deficits [52].”
Background
Application of Metabolomics in Alzheimer’s Disease
Wilkins, J. M., & Trushina, E. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2017.00719 · Cited by 268 · see citing works
“In all brain regions examined, levels of the neurotransmitter dopamine were altered in AD compared to NTG mice similar to that observed in AD patients (128, 138, 139).”
Result
Dopamine and Dopamine Receptors in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis
Pan, X., Kaminga, A. C., Wen, S. W., Wu, X., Acheampong, K., & Liu, A. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00175 · Cited by 269 · see citing works
“For instance, it is widely accepted that dopamine, which derives from the ventral tegmental area (VTA) dopaminergic neurons, modulates and projects mainly cerebral cortex, nucleus accumbens and hippocampal functions, including control of voluntary movement, memory and synaptic plasticity (Nobili et al., 2017).”
Background
The biological pathways of Alzheimer disease: a review
Calabrò, M., Rinaldi, C., Santoro, G., & Crisafulli, C. (2020) · AIMS neuroscience · doi:10.3934/neuroscience.2021005 · Cited by 271 · see citing works
“In AD, loss of 5-HT results in depression, anxiety and agitation [260], dysregulation of DA release leads to reward-mediated memory formation deficits [261], and low level of NE impairs spatial memory function [262].”
Background
Modifiable Risk Factors for Alzheimer’s Disease
Edwards III, G. A., Gamez, N., Escobedo Jr., G., Calderon, O., & Moreno-Gonzalez, I. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00146 · Cited by 253 · see citing works
Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases
Ai, X., Yu, P., Peng, L., Luo, L., Liu, J., Li, S., Lai, X., Luan, F., & Meng, X. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.762654 · Cited by 222 · see citing works
“Additionally, neuronal loss and cerebral blood flow contributed to dysfunction in memory and reward systems in AD (Dai et al., 2009; Nobili et al., 2017).”
Background
Challenges for Alzheimer's Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects
Frozza, R. L., Lourenco, M. V., & Felice, F. G. D. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00037 · Cited by 202 · see citing works
“…that inflammation and apoptosis take place in the ventral tegmental area, causing selective degeneration of the dopaminergic nuclei before senile plaque deposition, tangles or any sign of neuronal loss in cortical and hippocampal regions in a transgenic mouse model of AD (Nobili et al., 2017).”
BackgroundInfluential
Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease
Krashia, P., Cordella, A., Nobili, A., La Barbera, L., Federici, M., Leuti, A., Campanelli, F., Natale, G., Marino, G., Calabrese, V., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11928-w · Cited by 188 · see citing works
Self-citation
The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain
Gąsiorowska, A., Wydrych, M., Drapich, P., Zadrożny, M., Steczkowska, M., Niewiadomski, W., & Niewiadomska, G. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.654931 · Cited by 192 · see citing works
GLP-1 Receptor Signaling in Astrocytes Regulates Fatty Acid Oxidation, Mitochondrial Integrity, and Function
Timper, K., del Río-Martín, A., Cremer, A. L., Bremser, S., Alber, J., Giavalisco, P., Varela, L., Heilinger, C., Nolte, H., Trifunovic, A., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.001 · Cited by 170 · see citing works
Diagnostic contribution and therapeutic perspectives of transcranial magnetic stimulation in dementia
Lazzaro, V. D., Bella, R., Benussi, A., Bologna, M., Borroni, B., Capone, F., Chen, K.-H. S., Chen, R. E., Chistyakov, A. V., Claßen, J., et al. (2021) · Clinical Neurophysiology · doi:10.1016/j.clinph.2021.05.035 · Cited by 153 · see citing works
Impaired adult neurogenesis is an early event in Alzheimer’s disease neurodegeneration, mediated by intracellular Aβ oligomers
Scopa, C., Marrocco, F., Latina, V., Ruggeri, F., Corvaglia, V., Regina, F. L., Ammassari‐Teule, M., Middei, S., Amadoro, G., Meli, G., et al. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-019-0409-3 · Cited by 146 · see citing works
Precision drug delivery to the central nervous system using engineered nanoparticles
Gao, J., Xia, Z. J., Gunasekar, S., Jiang, C., Karp, J. M., & Joshi, N. (2024) · Nature Reviews Materials · doi:10.1038/s41578-024-00695-w · Cited by 162 · see citing works
“For instance, degeneration of dopaminergic neurons in the substantia nigra is usually associated with PD and HD 30–32 , whereas degeneration in the hippocampus is linked to AD 33,34 .”
Copper Induces Cognitive Impairment in Mice via Modulation of Cuproptosis and CREB Signaling
Zhang, Y., Zhou, Q., Lu, L., Su, Y., Shi, W., Zhang, H., Liu, R., Pu, Y., & Yin, L. (2023) · Nutrients · doi:10.3390/nu15040972 · Cited by 134 · see citing works
“Neuronal loss contributes to memory deficits and cognitive impairment [33,34].”
Background
Tetrahydrobioterin (BH4) pathway: from metabolism to neuropsychiatry
Fanet, H., Capuron, L., Castanon, N., Calon, F., & Vancassel, S. (2021) · Current Neuropharmacology · doi:10.2174/1570159x18666200729103529 · Cited by 134 · see citing works
“The dopaminergic system is also altered in AD, with a reduction of DA, main metabolites, and dopamine receptors [208, 209].”
Background
Dopaminergic Regulation of Innate Immunity: a Review
Pinoli, M., Marino, F., & Cosentino, M. (2017) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-017-9749-2 · Cited by 130 · see citing works
Diabetes and Cognitive Impairment: A Role for Glucotoxicity and Dopaminergic Dysfunction
Pignalosa, F. C., Desiderio, A., Mirra, P., Nigro, C., Perruolo, G., Ulianich, L., Formisano, P., Bèguinot, F., Miele, C., Napoli, R., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212366 · Cited by 129 · see citing works
“Moreover, impaired DA transmission was observed in diseases featuring cognitive deficit, such as Alzheimer’s disease [87], autism [88], and Huntington’s chorea [89].”
Background
Infectious agents and Alzheimer's disease
Piekut, T., Hurła, M., Banaszek, N., Szejn, P., Dorszewska, J., Kozubski, W., & Prendecki, M. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2102073 · Cited by 123 · see citing works
Dopamine-dependent early synaptic and motor dysfunctions induced by α-synuclein in the nigrostriatal circuit
Tozzi, A., Sciaccaluga, M., Loffredo, V., Megaro, A., Ledonne, A., Cardinale, A., Federici, M., Bellingacci, L., Paciotti, S., Ferrari, E. S., et al. (2021) · Brain · doi:10.1093/brain/awab242 · Cited by 127 · see citing works
“Amperometric detection of electrically-evoked DA release was performed in acute brain slices containing the dorsal striatum as described previously.(28,29) Briefly, the DA-recording carbon fibre electrode was positioned near a bipolar Ni/Cr stimulating electrode, to a depth of 50–150 lm into the coronal slice.”
MethodSelf-citation
Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease
Wong, K. Y., Roy, J., Fung, M., Heng, B. C., Zhang, C., & Lim, L. W. (2020) · Aging and Disease · doi:10.14336/ad.2019.1125 · Cited by 119 · see citing works
“A recent study revealed that selective apoptosis was involved only in the VTA, and not SNpc, hippocampus, neocortex, and locus ceruleus (LC) of Tg mice in the pre-plaque stage of AD [39].”
Background
Dopamine: an immune transmitter
Broome, S. T., Louangaphay, K., Keay, K. A., Leggio, G. M., Musumeci, G., & Castorina, A. (2020) · Neural Regeneration Research · doi:10.4103/1673-5374.284976 · Cited by 109 · see citing works
Biochemical Markers in Alzheimer’s Disease
Rabbito, A., Dulewicz, M., Kulczyńska‐Przybik, A., & Mroczko, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21061989 · Cited by 105 · see citing works
“Besides these results obtained in AD patients, recently, a study using an animal model of AD, investigated the effects of neuronal dopamine loss in memory and reward dysfunction [38].”
BackgroundResult
Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer’s Disease in Humans
Marco, M. D., & Venneri, A. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-171018 · Cited by 103 · see citing works
Roles of Selenoproteins in Brain Function and the Potential Mechanism of Selenium in Alzheimer’s Disease
Zhang, Z.-H., & Song, G.-L. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.646518 · Cited by 106 · see citing works
Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease
La Barbera, L., Vedele, F., Nobili, A., Krashia, P., Spoleti, E., Latagliata, E. C., Cutuli, D., Cauzzi, E., Marino, R., Viscomi, M. T., et al. (2021) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102031 · Cited by 98 · see citing works
“Loss of tyrosine hydroxylase positive (TH) terminals in the dorsal hippocampus and NAc shell results in a prominent drop of DA outflow to these projection areas and in a deficit of synaptic plasticity, followed by impairments in memory and reward performance in 6-month-old Tg2576 mice (Cordella et al., 2018; Nobili et…”
BackgroundInfluentialSelf-citation
The role of dopaminergic midbrain in Alzheimer’s disease: Translating basic science into clinical practice
D’Amelio, M., Puglisi‐Allegra, S., & Mercuri, N. B. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.01.016 · Cited by 95 · see citing works
Self-citation
Tau-driven degeneration of sleep- and wake-regulating neurons in Alzheimer’s disease
Lew, C. H., Petersen, C., Neylan, T. C., & Grinberg, L. T. (2021) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2021.101541 · Cited by 95 · see citing works
In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer’s disease
Serra, L., D'Amelio, M., Di Domenico, C., Dipasquale, O., Marra, C., Mercuri, N. B., Caltagirone, C., Cercignani, M., & Bozzali, M. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.08.012 · Cited by 91 · see citing works
“In line with our hypothesis and with previous animal work (Nobili et al., 2017), we found evidence of VTA disconnection with the right parietal lobe (BA7) in a-MCI.”
BackgroundResultInfluentialSelf-citation
Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-β Aggregation, Oxidative Stress, and Inflammation in Alzheimer’s Disease
Nam, E., Derrick, J. S., Lee, S., Kang, J., Han, J., Lee, S. J. C., Chung, S. W., & Lim, M. H. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00122 · Cited by 88 · see citing works
Neuroprotective effect of quercetin nanoparticles: A possible prophylactic and therapeutic role in alzheimer’s disease
Rifaai, R. A., Mokhemer, S. A., Saber, E. A., El‐Aleem, S. A. A., & El‐Tahawy, N. F. G. (2020) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2020.101795 · Cited by 88 · see citing works
SGLT2 inhibitors: a novel therapy for cognitive impairment via multifaceted effects on the nervous system
Mei, J., Li, Y., Niu, L., Liang, R., Tang, M., Cai, Q., Xu, J., Zhang, D., Yin, X., Liu, X., et al. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00431-y · Cited by 85 · see citing works
“…the level of dynamin-related protein 1 (Drp1) in mitochondria within neurons and stimulates the overproduction of ROS, resulting in impaired mitochondrial morphology and function, which in turn leads to neuron apoptosis dopaminergic neurons then leads to memory and reward dysfunction [62].”
Background
Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer’s disease
Cordella, A., Krashia, P., Nobili, A., Pignataro, A., La Barbera, L., Viscomi, M. T., Valzania, A., Keller, F., Ammassari-Teule, M., Mercuri, N. B., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.05.006 · Cited by 82 · see citing works
Role of sex and high-fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer’s disease
Robison, L. S., Gannon, O. J., Thomas, M. A., Salinero, A. E., Abi‐Ghanem, C., Poitelon, Y., Belin, S., & Zuloaga, K. L. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01956-5 · Cited by 78 · see citing works
“In AD mice, this is associated with attenuated dopaminergic output in the hippocampus and nucleus accumbens, as well as altered neural and behavioral reactivity to reward, including palatable foods [131, 134].”
Background
The Hyperactivity–Impulsivity–Irritiability–Disinhibition–Aggression–Agitation Domain in Alzheimer’s Disease: Current Management and Future Directions
Keszycki, R. M., Fisher, D. W., & Dong, H.-X. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01109 · Cited by 62 · see citing works
“Some degeneration in the mesolimbic dopamine circuitry has also been described and may contribute to these symptoms (Lyness, 2003; Nobili et al., 2017; D’Amelio et al., 2018).”
Background
Functionalization strategies of polymeric nanoparticles for drug delivery in Alzheimer’s disease: Current trends and future perspectives
La Barbera, L., Mauri, E., D’Amelio, M., & Gori, M. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.939855 · Cited by 74 · see citing works
“, 2021), cholinergic (Terry and Buccafusco, 2003; Chen and Mobley, 2019), and dopaminergic degeneration (Nobili et al., 2017; Cordella et al., 2018; De Marco and Venneri, 2018; Serra et al., 2018, 2021; Bozzali et al., 2019; Iaccarino et al., 2020; Venneri and De Marco, 2020; La Barbera et al., 2021; Sala et al., 2021…”
BackgroundSelf-citation
Amyloid β-Induced Upregulation of Nav1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer’s Disease Mouse Model
Ciccone, R., Franco, C., Piccialli, I., Boscia, F., Casamassa, A., de Rosa, V., Cepparulo, P., Cataldi, M., Annunziato, L., & Pannaccione, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-50018-1 · Cited by 75 · see citing works
Methamphetamine abuse disturbs the dopaminergic system to impair hippocampal-based learning and memory: An overview of animal and human investigations
Shukla, M., & Vincent, B. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.09.016 · Cited by 72 · see citing works
The role of dopamine in NLRP3 inflammasome inhibition: Implications for neurodegenerative diseases
Possemato, E., Barbera, L. L., Nobili, A., Krashia, P., & D’Amelio, M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101907 · Cited by 75 · see citing works
Self-citation
Unifying Hypothesis of Dopamine Neuron Loss in Neurodegenerative Diseases: Focusing on Alzheimer's Disease
Krashia, P., Nobili, A., & D’Amelio, M. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00123 · Cited by 70 · see citing works
Self-citation
Dexmedetomidine Activation of Dopamine Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice
Qiu, G., Wu, Y., Yang, Z., Li, L., Zhu, X., Wang, Y., Sun, W., Dong, H., Li, Y., & Hu, J. (2020) · Anesthesiology · doi:10.1097/aln.0000000000003347 · Cited by 73 · see citing works
Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice
Cao, S., Fisher, D. W., Rodríguez, G., Yu, T., & Dong, H. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-020-02054-2 · Cited by 67 · see citing works
Branched-Chain Amino Acids Are Linked with Alzheimer’s Disease-Related Pathology and Cognitive Deficits
Siddik, M. A. B., Mullins, C. A., Kramer, A., Shah, H., Gannaban, R. B., Zabet-Moghaddam, M., Huebinger, R. M., Hegde, V. K., MohanKumar, S. M. J., MohanKumar, P. S., et al. (2022) · Cells · doi:10.3390/cells11213523 · Cited by 68 · see citing works
Monoaminergic System Modulation in Depression and Alzheimer’s Disease: A New Standpoint?
Morgese, M. G., & Trabace, L. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00483 · Cited by 69 · see citing works
Mesoporous chitosan based conformable and resorbable biostrip for dopamine detection
Kafi, M. A., Paul, A., Vilouras, A., et al. (2019) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2019.111781 · Cited by 68 · see citing works
A multitude of signaling pathways associated with Alzheimer's disease and their roles in AD pathogenesis and therapy
Gadhave, K., Kumar, D., Uversky, V. N., & Giri, R. (2020) · Medicinal Research Reviews · doi:10.1002/med.21719 · Cited by 70 · see citing works
“Nobili et al.(157) recently reported the loss of neurons in”
Background
In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases
Sala, A., Caminiti, S. P., Presotto, L., Pilotto, A., Liguori, C., Chiaravalloti, A., Garibotto, V., Frisoni, G. B., D’Amelio, M., Paghera, B., et al. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00925-1 · Cited by 66 · see citing works
“Some authors have suggested that the peculiar physiology of midbrain ventrategmental dopaminergic neurons, per se, might render those dopaminergic neurons particularly vulnerable to amyloid pathology in AD [36].”
BackgroundResultSelf-citation
Multi-target-directed therapeutic strategies for Alzheimer's disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition
Yoo, J., Lee, J., Ahn, B., Han, J., & Lim, M. H. (2025) · Chemical Science · doi:10.1039/d4sc06762b · Cited by 74 · see citing works
Dopaminergic regulation of hippocampal plasticity, learning, and memory
Tsetsenis, T., Broussard, J. I., & Dani, J. A. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2022.1092420 · Cited by 68 · see citing works
“This notion finds further support from studies using a mouse model of early-stage Alzheimer’s disease (Nobili et al., 2017).”
Result
Protection of MCC950 against Alzheimer's disease via inhibiting neuronal pyroptosis in SAMP8 mice
Li, J., Zhuang, L., Luo, X., Liang, J., Sun, E., & He, Y. (2020) · Experimental Brain Research · doi:10.1007/s00221-020-05916-6 · Cited by 66 · see citing works
Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease
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An Expanded Narrative Review of Neurotransmitters on Alzheimer’s Disease: The Role of Therapeutic Interventions on Neurotransmission
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“Degeneration of dopaminergic neurons in the VTA causes memory deficits and loss of consciousness in AD [115].”
Shared Causal Paths underlying Alzheimer’s dementia and Type 2 Diabetes
Hu, Z., Jiao, R., Wang, P., Zhu, Y., Zhao, J., Jager, P. L. D., Bennett, D. A., Li, J., & Xiong, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-60682-3 · Cited by 63 · see citing works
Effect of Rotigotine vs Placebo on Cognitive Functions Among Patients With Mild to Moderate Alzheimer Disease
Koch, G., Motta, C., Bonnı̀, S., Pellicciari, M. C., Picazio, S., Casula, E. P., Maiella, M., Lorenzo, F. D., Ponzo, V., Ferrari, C., et al. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2020.10372 · Cited by 63 · see citing works
Irisin: A Multifaceted Hormone Bridging Exercise and Disease Pathophysiology
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“…dopamine signaling, irisin, and AD is further suggested not only by the evidence that early neuron loss in the VTA is reported in AD-like mice [157] and the dopamine-evoked neprilysin activity [166] but also by the captivating finding that irisin was able to reduce A β pathology using a…”
Self-citation
Dopamine neuron degeneration in the Ventral Tegmental Area causes hippocampal hyperexcitability in experimental Alzheimer’s Disease
Spoleti, E., Barbera, L. L., Cauzzi, E., Paolis, M. L. D., Saba, L., Marino, R., Sciamanna, G., Lazzaro, V. D., Keller, F., Nobili, A., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02408-9 · Cited by 61 · see citing works
Self-citation
Targeting Alzheimer's disease with gene and cell therapies
Loera‐Valencia, R., Piras, A., Ismail, M.-A.-M., Manchanda, S., Eyjolfsdottir, H., Saido, T. C., Johansson, J., Eriksdotter, M., Winblad, B. G., & Nilsson, P. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12759 · Cited by 57 · see citing works
Cerebrospinal fluid catecholamines in Alzheimer’s disease patients with and without biological disease
Henjum, K., Watne, L. O., Godang, K., Halaas, N. B., Eldholm, R. S., Blennow, K., Zetterberg, H., Saltvedt, I. T., Bollerslev, J., & Knapskog, A. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01901-5 · Cited by 56 · see citing works
“In young transgenic mice modeling AD neuronal loss in the VTA was followed by astrogliosis [23] suggesting inflammation also in this area as an early event in the pathology.”
Background
Emotion Processing Dysfunction in Alzheimer’s Disease: An Overview of Behavioral Findings, Systems Neural Correlates, and Underlying Neural Biology
Chaudhary, S., Zhornitsky, S., Chao, H. H., van Dyck, C. H., & Li, C.-S. R. (2022) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/15333175221082834 · Cited by 61 · see citing works
Behavioral and neuropsychiatric disorders in Alzheimer's disease
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“In addi374 tion, it has been recently determined that the loss of 375 dopamine affects memory dysfunction in a transgenic 376 mouse of AD [111].”
Glucose metabolism: A link between traumatic brain injury and Alzheimer’s disease
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Using high-dimensional machine learning methods to estimate an anatomical risk factor for Alzheimer's disease across imaging databases
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Dopaminergic dysfunction in the 3xTg-AD mice model of Alzheimer’s disease
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“Coinciding with our findings, researchers found that in an animal model of AD, degeneration of ventral tegmental area dopaminergic neurons at pre-plaque stages causes memory defects (Nobili et al. 2017).”
Result
Bradykinesia in Alzheimer’s disease and its neurophysiological substrates
Bologna, M., Guerra, A., Colella, D., Cioffi, E., Paparella, G., Vita, A. D., D’Antonio, F., Trebbastoni, A., & Berardelli, A. (2020) · Clinical Neurophysiology · doi:10.1016/j.clinph.2019.12.413 · Cited by 55 · see citing works
Correlation between cortical gene expression and resting‐state functional network centrality in healthy young adults
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“Dopaminergic neurotransmission dysfunction has been found to be involved in the pathogenesis of several psychiatric and neurological disorders (Ko & Strafella, 2012) such as MDD (Pogarell et al., 2006), AD (Nobili et al., 2017), and SCZ (Chuhma, Mingote, Kalmbach, Yetnikoff, & Rayport, 2017).”
Background
Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease
Chen, A. P. F., Chen, L., Kim, T. A., & Xiong, Q. (2021) · Biomedicines · doi:10.3390/biomedicines9060647 · Cited by 55 · see citing works
Physical Exercise as Disease-Modifying Alternative against Alzheimer’s Disease: A Gut–Muscle–Brain Partnership
Cutuli, D., Decandia, D., Giacovazzo, G., & Coccurello, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914686 · Cited by 58 · see citing works
Self-citation
Synaptic modification by L-theanine, a natural constituent in green tea, rescues the impairment of hippocampal long-term potentiation and memory in AD mice
Zhu, G., Yang, S., Xie, Z., & Wan, X. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.06.030 · Cited by 53 · see citing works
“Moreover, several studies have reported that DA activation could repair memory impairment in AD mice (Hao et al., 2015; Nobili et al., 2017).”
More than Addiction—The Nucleus Accumbens Contribution to Development of Mental Disorders and Neurodegenerative Diseases
Bayassi-Jakowicka, M., Lietzau, G., Czuba, E., Patrone, C., & Kowiański, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052618 · Cited by 52 · see citing works
“Studies on an animal model of AD (Tg2576 mice) have shown a decreased number of dopaminergic cells in the VTA due to their apoptotic death [92].”
Background
Identification of Differentially Expressed Profiles of Alzheimer's Disease Associated Circular RNAs in a Panax Notoginseng Saponins-Treated Alzheimer's Disease Mouse Model
Huang, J.-L., Xu, Z.-H., Yang, S., Yu, C., Zhang, F., Qin, M.-C., Zhou, Y., Zhong, Z.-G., & Wu, D. (2018) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2018.10.010 · Cited by 51 · see citing works
Brain Inflammation Connects Cognitive and Non-Cognitive Symptoms in Alzheimer’s Disease
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Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer’s disease
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“Disruptions in tyrosine metabolism and neurotransmitter synthesis have been reported in various neurological disorders, including AD [48, 71], and changes in tyrosine phosphorylation of proteins involved in synaptic plasticity have also been observed [46].”
Background
Upregulation of Ca2+-binding proteins contributes to VTA dopamine neuron survival in the early phases of Alzheimer’s disease in Tg2576 mice
Barbera, L. L., Nobili, A., Cauzzi, E., Paoletti, I., Federici, M., Saba, L., Giacomet, C., Marino, R., Krashia, P., Melone, M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00580-6 · Cited by 49 · see citing works
“This confirms our earlier observations from Tg2576 mice that the degenerative process is selective for VTA neurons, whereas SNpc TH+ neurons are intact, at least until 6 months of age, with no evidence of either apoptosis or neuroinflammation, unlike the VTA [21].”
BackgroundMethodResultInfluentialSelf-citation
Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice
Fertan, E., Stover, K. R., Brant, M. G., Stafford, P. M., Kelly, B., Diez‐Cecilia, E., Wong, A. A., Weaver, D. F., & Brown, R. E. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01044 · Cited by 48 · see citing works
Alterations in dopamine system and in its connectivity with serotonin in a rat model of Alzheimer’s disease
Ceyzériat, K., Gloria, Y., Tsartsalis, S., Fossey, C., Cailly, T., Fabis, F., Millet, P., & Tournier, B. B. (2021) · Brain Communications · doi:10.1093/braincomms/fcab029 · Cited by 47 · see citing works
“3C) [two-way ANOVA, treatment group interaction: F(4,53) 1⁄4 3.”
Method
Determinants of approved acetylcholinesterase inhibitor response outcomes in Alzheimer’s disease: relevance for precision medicine in neurodegenerative diseases
Lista, S., Vergallo, A., Teipel, S. J., Lemercier, P., Giorgi, F. S., Gabelle, A., Garaci, F., Mercuri, N. B., Babiloni, C., Gaire, B. P., et al. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101819 · Cited by 46 · see citing works
Self-citation
Ginsenoside Rb1 prevents MPTP-induced changes in hippocampal memory via regulation of the α-synuclein/PSD-95 pathway
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Cell-type-specific disruption of PERK-eIF2α signaling in dopaminergic neurons alters motor and cognitive function
Longo, F., Mancini, M., Ibraheem, P. L., Aryal, S., Mesini, C., Patel, J. C., Penhos, E., Rahman, N., Mamcarz, M., Santini, E., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01099-w · Cited by 47 · see citing works
“function contributes to cognitive deficits in AD [47].”
BackgroundInfluential
Altered Neurochemistry in Alzheimer’s Disease: Targeting Neurotransmitter Receptor Mechanisms and Therapeutic Strategy
Kaur, S., DasGupta, G., & Singh, S. (2019) · Neurophysiology · doi:10.1007/s11062-019-09823-7 · Cited by 45 · see citing works
Pathophysiological Mechanisms of Cognitive Impairment and Neurodegeneration by Toxoplasma gondii Infection
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Cannabidiol regulates CB1‐pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of Aβ pathology models
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Potential Pathways for Circadian Dysfunction and Sundowning-Related Behavioral Aggression in Alzheimer’s Disease and Related Dementias
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K284-6111 alleviates memory impairment and neuroinflammation in Tg2576 mice by inhibition of Chitinase-3-like 1 regulating ERK-dependent PTX3 pathway
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Stress-induced alterations of mesocortical and mesolimbic dopaminergic pathways
Quessy, F., Bittar, T., Blanchette, L. J., Lévesque, M., & Labonté, B. (2021) · Scientific Reports · doi:10.1038/s41598-021-90521-y · Cited by 42 · see citing works
“Finally, investigating these effects by layer [superficial (II–III) or deep (V–VI)] revealed a trend toward a significant effect of CSDS on pERK expression in the superficial layers (II–III) of the mPFC from males and females (Phenotype main effect: F(2,27) = 3.”
Background
Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer’s disease
Tsui, K. C., Roy, J., Chau, S. C., Wong, K.-H., Shi, L., Poon, C. H., Wang, Y., Strekalova, T. V., Aquili, L., Chang, R. C., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.964336 · Cited by 44 · see citing works
“The deposition of Aβ in these regions can disrupt dopaminergic-regulated reward memory processing in 3xTg-AD and Tg2576 mouse models (Nobili et al., 2017; Gloria et al., 2021).”
Background
The dopaminergic system promotes neprilysin-mediated degradation of amyloid-β in the brain
Watamura, N., Kakiya, N., Fujioka, R., Kamano, N., Takahashi, M., Nilsson, P., Saito, T., Iwata, N., Fujisawa, S., & Saido, T. C. (2024) · Science Signaling · doi:10.1126/scisignal.adk1822 · Cited by 44 · see citing works
“…mice [an AD mouse model overexpressing the APP gene containing the Swedish mutation ( 39 )], the loss of DAergic neurons in the VTA, but not in the substantia nigra pars compacta, precedes the deposition of A β plaques ( 40 – 42 ), suggesting specific vulnerability of VTA DAergic neurons in AD.”
Background
Oxidative stress and neurodegeneration: The possible contribution of quinone reductase 2
Cassagnes, L., Chhour, M., Pério, P., Sudor, J., Gayon, R., Ferry, G., Boutin, J. A., Nepveu, F., & Reybier, K. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.03.002 · Cited by 42 · see citing works
Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer’s disease models
Corsetti, V., Borreca, A., Latina, V., Giacovazzo, G., Pignataro, A., Krashia, P., Natale, F., Cocco, S., Rinaudo, M., Malerba, F., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa039 · Cited by 41 · see citing works
Self-citation
Mind-Body Exercise Modulates Locus Coeruleus and Ventral Tegmental Area Functional Connectivity in Individuals With Mild Cognitive Impairment
Liu, J., Tao, J., Xia, R., Li, M., Huang, M., Li, S., Chen, X., Wilson, G., Park, J., Zheng, G., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.646807 · Cited by 44 · see citing works
<i>In vivo</i> MRI Structural and PET Metabolic Connectivity Study of Dopamine Pathways in Alzheimer’s Disease
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“As mentioned in the introduction, both hippocampal formation and VST are innervated by VTA dopaminergic projections, the degeneration of which has been shown to produce lower DA outflow, equally affecting the hippocampus and VST in AD transgenic animal models [11].”
BackgroundInfluential
Walking, Running, Swimming: An Analysis of the Effects of Land and Water Aerobic Exercises on Cognitive Functions and Neural Substrates
Serra, L., Petrosini, L., Mandolesi, L., Bonarota, S., Balsamo, F., Bozzali, M., Caltagirone, C., & Gelfo, F. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph192316310 · Cited by 43 · see citing works
“It has been recently demonstrated that dopaminergic depletion plays a key role in the onset of cognitive and brain dysfunctions observed since the early stages of neurodegenerative diseases, such as Alzheimer’s Disease, both in animal [104] as well as in clinical [105,106] studies.”
BackgroundSelf-citation
Growth Control of Metal–Organic Framework Films on Marine Biological Carbon and Their Potential-Dependent Dopamine Sensing
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Effects of transcranial magnetic stimulation on neurobiological changes in Alzheimer's disease (Review)
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“The loss and decrease in dopamine content and its receptors are frequently reported in patients with AD, causing motor impairment and cognitive decline (99,103,104).”
Background
Monitoring synaptic pathology in Alzheimer’s disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives
Lista, S., Santos‐Lozano, A., Emanuele, E., Mercuri, N. B., Gabelle, A., López‐Ortiz, S., Martín-Hernández, J., Maisto, N., Imbimbo, C., Caraci, F., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-023-02376-6 · Cited by 42 · see citing works
“In particular, the role of dopamine has been proved in a validated AD mouse model [16] and con ﬁ rmed in AD patients by different imaging tools [17 – 19].”
Self-citation

Morphological parameters of the heterogeneity of the substantia nigra in elderly men and women
Николаевич, С. В., Худоерков, Р. М., Воронков, Д. Н., et al. (2015) · Russian Journal of Archive of Pathology · doi:10.17116/patol201577451-54 · Cited by 3 · see citing works
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Authors: Nobili, A., Latagliata, E. C., Viscomi, M. T., Cavallucci, V., Cutuli, D., Giacovazzo, G., Krashia, P., Rizzo, F. R., Marino, R., Federici, M., De Bartolo, P., Aversa, D., Dell’Acqua, M. C., Cordella, A., Sancandi, M., Keller, F., Petrosini, L., Puglisi-Allegra, S., Mercuri, N. B., Coccurello, R., Berretta, N., & D’Amelio, M.
Affiliations: Università Campus Bio-Medico (IT)
Fondazione Santa Lucia (IT)
Università Cattolica del Sacro Cuore (IT)
University of Rome Tor Vergata (IT)
Sapienza University of Rome (IT)
Corresponding author: D’Amelio, Marcello
ORCID: Nobili, Annalisa
Latagliata, Emanuele Claudio
Viscomi, Maria Teresa
Cavallucci, Virve
Cutuli, Debora
Giacovazzo, Giacomo
Krashia, Paraskevi
Rizzo, Francesca Romana
Federici, Mauro
Cordella, Alberto
Keller, Flavio
Petrosini, Laura
Mercuri, Nicola Biagio
Coccurello, Roberto
Berretta, Nicola
D’Amelio, Marcello
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2017-04-03
Volume: 8
Issue: 1
Pages: 14727-14727
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/ncomms14727
PMC: PMC5382255
OpenAlex: W2604754546
Semantic Scholar: c54223a18517b1d02e736ed02d7bad7f1eb4adad
Cited by: 514
References: 69
Citations by year: 2026: 46 · 2025: 75 · 2024: 81 · 2023: 59 · 2022: 51 · 2021: 67 · 2020: 59 · 2019: 35 · 2018: 33 · 2017: 8
FWCI: 27.33
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature Communications (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Alzheimer's Association (NIRG-11-204588)
Ministero della Salute (GR-2011-02351457)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: Alzheimer's disease, dopaminergic neuron loss, ventral tegmental area, substantia nigra pars compacta, APPswe, amyloid precursor protein, midbrain dopamine, hippocampal synaptic plasticity, CA1, memory impairment, nucleus accumbens shell
MeSH terms: Alzheimer Disease, Animals, Disease Models, Animal, Dihydroxyphenylalanine, Food, Hippocampus, Inflammation, Memory, Mice, Transgenic, Nerve Degeneration, Neuronal Plasticity, Nucleus Accumbens, Reward, Selegiline, Cell Death, Apoptosis, Ventral Tegmental Area, Dendritic Spines, Plaque, Amyloid, Dopaminergic Neurons

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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

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