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Cited by 98Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 165 of the 172 references it cites were found in a registry or an index; none of the 91 sources its claims cite is checked for support yet.

Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease

Open access
La Barbera, Livia, Vedele, Francescangelo, Nobili, Annalisa, Krashia, Paraskevi, Spoleti, Elena, Latagliata, Emanuele Claudio, Cutuli, Debora, Cauzzi, Emma, Marino, Ramona, Viscomi, Maria Teresa, Petrosini, Laura, Puglisi- Allegra, Stefano, Melone, Marcello, Keller, Flavio, Mercuri, Nicola Biagio, Conti, Fiorenzo, D’Amelio, Marcello·2021·Progress in Neurobiology
DOI 10.1016/j.pneurobio.2021.102031
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Abstract

What happens precociously to the brain destined to develop Alzheimer's Disease (AD) still remains to be elucidated and this is one reason why effective AD treatments are missing. Recent experimental and clinical studies indicate that the degeneration of the dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA) could be one of the first events occurring in AD. However, the causes of the increased vulnerability of DA neurons in AD are missing. Here, we deeply investigate the physiology of DA neurons in the VTA before, at the onset, and after onset of VTA neurodegeneration. We use the Tg2576 mouse model of AD, overexpressing a mutated form of the human APP, to identify molecular targets that can be manipulated pharmacologically. We show that in Tg2576 mice, DA neurons of the VTA at the onset of degeneration undergo slight but functionally relevant changes in their electrophysiological properties and cell morphology. Importantly, these changes are associated with accumulation of autophagosomes, suggestive of a dysfunctional autophagy, and with enhanced activation of c-Abl, a tyrosine kinase previously implicated in the pathogenesis of neurodegenerative diseases. Chronic treatment of Tg2576 mice with Nilotinib, a validated c-Abl inhibitor, reduces c-Abl phosphorylation, improves autophagy, reduces Aβ levels and - more importantly - prevents degeneration as well as functional and morphological alterations in DA neurons of the VTA. Interestingly, the drug prevents the reduction of DA outflow to the hippocampus and ameliorates hippocampal-related cognitive functions. Our results strive to identify early pathological brain changes in AD, to provide a rational basis for new therapeutic interventions able to slow down the disease progression.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In Tg2576 Alzheimer’s disease mice, ventral tegmental area (VTA) dopaminergic neurons show early hyperexcitability, autophagosome accumulation, and increased c-Abl activation before/at degeneration onset. Chronic Nilotinib treatment reduces c-Abl phosphorylation, improves autophagy, lowers Aβ, prevents DA neuron degeneration and hippocampal DA loss, and rescues novel object recognition memory.

Key findings

  • VTA DA neurons in Tg2576 mice were normal at 1 month, but at 3 months showed increased spontaneous firing frequency (p = 0.044), which became more prominent at 6 months (p = 0.0007); at 6 months they also showed increased evoked firing at +200 pA (*p = 0.023) and a more negative AP threshold (*p = 0.032).
  • At 3 months, Tg2576 VTA DA neurons had increased autophagosome density (p = 0.0013), increased LC3II/LC3I ratio (*p = 0.025), and increased midbrain p-c-Abl(Y412)/c-Abl (*p = 0.039), with no changes in hippocampus, amygdala, or cortex.
  • Nilotinib (1 mg/kg i.p., alternate days from 45 days of age) reduced midbrain c-Abl phosphorylation (*p < 0.001), reduced LC3II/LC3I (*p = 0.034), reduced yellow LC3 puncta (p = 0.002), increased the red/yellow puncta ratio (p = 0.004), and reduced Aβ in VTA TH+ neurons (p = 0.004).
  • In 6-month-old Tg2576 mice, Nilotinib prevented DA neuron loss (Tg Veh vs Tg Nil *p = 0.045), prevented lateral VTA soma area/perimeter reductions (*p = 0.026 and *p = 0.042), increased hippocampal DA levels at several microdialysis time points (*p = 0.030, *p = 0.050, *p = 0.040), and prevented novel object recognition deficits at 1 h (*p = 0.028) and 24 h (*p = 0.016).

Methods

  • Heterozygous Tg2576 mice and WT littermates of either sex were studied at 1, 3, and 6 months; Nilotinib or vehicle was given i.p. on alternate days starting at 45 days of age.
  • The study combined whole-cell patch-clamp and single-unit extracellular recordings, morphology/stereology, transmission electron microscopy, AAV2/9-mCherry-GFP-LC3 autophagy-flux imaging, immunoblotting, microdialysis, and the Novel Object Recognition Test.
  • Statistical analysis used two-way/repeated-measures/three-way ANOVA with Tukey or Sidak post hoc tests, plus parametric or non-parametric tests; data collection was blinded to genotype or treatment.

Limitations

  • The paper states that the experiments do not permit discernment of how phosphorylated c-Abl increases in the midbrain or the precise mechanism linking c-Abl to selective DA neuron degeneration; whether degeneration starts locally in the midbrain and/or via dying-back from axonal terminals remains undefined.
  • The paper notes that it cannot exclude additional brain-region involvement in Nilotinib’s beneficial effects, since the drug produced a global reduction in Aβ levels; it also reports that lateral VTA DA neuron reduction at 6 months was a non-significant trend.
  • Evident from the text: this is a Tg2576 mouse study, and some procedures (AAV injection, microdialysis) used male mice only, which may limit generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.pneurobio.2021.102031

Cites

165 of 165 references verified0 citation errors · 0 not checkable

Statistics

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Verification

Claims the paper makes

0 of 91 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § A B S T R A C T · p. 1

    At the onset of degeneration, VTA DA neurons in Tg2576 mice undergo changes in cell morphology.

    “We show that in Tg2576 mice, DA neurons of the VTA at the onset of degeneration undergo slight but functionally relevant changes in their electrophysiological properties and cell morphology.”
    Quote in the paperSubstantial claim
  • Findingown data
    § A B S T R A C T · p. 1

    Chronic treatment of Tg2576 mice with Nilotinib prevents functional alterations in VTA DA neurons.

    “prevents degeneration as well as functional and morphological alterations in DA neurons of the VTA”
    Quote in the paperSubstantial claim
  • Findingown data
    § A B S T R A C T · p. 1

    Chronic treatment of Tg2576 mice with Nilotinib improves autophagy.

    “improves autophagy”
    Quote in the paperNot a substantial claim
  • Findingreasoning
    § A B S T R A C T · p. 1

    Nilotinib prevents the reduction of DA outflow to the hippocampus in Tg2576 mice.

    “the drug prevents the reduction of DA outflow to the hippocampus”
    • Also stated in: § 1. Introduction · p. 2 · plain
      “prevents the loss of DA outflow to the hippocampus”
    Quote in the paperSubstantial claim
  • Findingown data
    § A B S T R A C T · p. 1

    Chronic treatment of Tg2576 mice with Nilotinib prevents degeneration of VTA DA neurons.

    “prevents degeneration as well as functional and morphological alterations in DA neurons of the VTA”
    • Also stated in: § 1. Introduction · p. 2 · plain
      “blocking DA neuron degeneration”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 43
  • Probably not a substantial claim. 31
  • The quote only partly states this claim. 1

  • It may state two separate claims as one.

    Findingown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    DA neurons from 3-month-old Tg2576 mice display increased spontaneous firing frequency compared to WT, which becomes more prominent at 6 months, while no difference is seen at 1 month.

    “While at 1 month of age no differences could be seen between WT and Tg2576 neurons, DA neurons from 3- month-old Tg2576 mice displayed an increased spon­ taneous firing frequency, that became even more prominent at 6 months of age (Fig. 1A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    The increased excitability of 6-month-old Tg2576 DA neurons was strongly correlated with a significant shift of the AP threshold to more negative values and a faster deactivation of the AP.

    “On the other hand, it was strongly correlated with a significant shift of the AP threshold to more negative values in 6-month-old Tg2576 neurons (Fig. 1D,E), while we also observed a faster deactivation of the AP (Supplementary Table 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    In 1- and 3-month-old Tg2576 mice the ability of DA neurons to fire APs was unchanged compared to WT, but the firing rate was enhanced in 6-month-old Tg2576 mice.

    “In 1- and 3-month-old Tg2576 mice the ability of DA neurons to fire APs was unchanged compared to WT neurons, yet the firing rate was particularly enhanced in 6-month-­ old Tg2576 mice (Fig. 1C; Supplementary Fig. 1A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    There was no difference between genotypes in the magnitude of the Ih current at 1 and 3 months of age, while in 6-month-old Tg2576 DA cells the Ih current was reduced compared to WT neurons.

    “We did not observe any difference between genotypes in the magnitude of the Ih current at 1 and 3 months of age (Supplementary Fig. 2B), while in 6-month-old Tg2576 DA cells the Ih current was reduced compared to WT neurons (Fig. 2B).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    When SK current was plotted as current density relative to cell size, there was no difference compared to WT neurons at 3 or 6 months of age, and only a small reduction in neurons of younger Tg2576 animals.

    “Indeed, when the SK current was plotted as the current density relative to cell size, we found no difference compared to WT neurons at 3 or 6 months of age (Fig. 2A) and only a small reduction in neurons of younger Tg2576 animals (Supplementary Fig. 2A).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.5. Nilotinib prevents DA neuron degeneration in Tg2576 mice · p. 11

    Nilotinib had no effect in the DA neurons of the intermediate subfield of the VTA, where no morphological differences were observed between WT and Tg2576 neurons.

    “Conversely, Nilotinib had no effect in the DA neurons of the intermediate subfield of the VTA, where no morphological differences were observed between WT and Tg2576 neurons (Supplementary Fig. 4E, see also Fig. 3C).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    Basal (total) midbrain levels of c-Abl were unchanged between WT and Tg2576, but there was increased phosphorylation of c-Abl in Tg2576 mice.

    “Although the basal (total) midbrain levels of c-Abl were unchanged between WT and Tg2576, we observed an increased phos­ phorylation of c-Abl in Tg2576 mice (Fig. 4E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    No changes in LC3II/LC3I ratio were observed in these regions, indicating no alterations in the autophagic process, at least at this age.

    “Furthermore, we did not observe any changes in LC3II/LC3I ratio in these regions (Supplementary Fig. 3), indicating no alterations in the autophagic process, at least at this age.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.4. Nilotinib improves autophagy flux and reduces A β load in 3-monthold Tg2576 mice · p. 11

    In TH+ neurons from Nilotinib-treated Tg2576 mice, there was a reduction of yellow puncta, suggestive of a reduced accumulation of autophagosome vesicles, while red puncta per cell remained unchanged.

    “Interestingly, in TH + neurons from Nilotinib-treated Tg2576 mice we observed a reduction of yellow puncta (Fig. 5B), suggestive of a reduced accumulation of autophagosome vesicles, while red puncta per cell remained unchanged.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    Quantification of yellow puncta in VTA TH+ cells showed a significant increase in Tg2576, indicating an increase in autophagosome numbers, while the number of autophagolysosomes (red puncta) was invariant.

    “Quantification of yellow puncta in VTA TH + cells showed a significant increase in Tg2576, indicating an increase in autophagosome numbers, while the number of autophago­ lysosomes (red puncta) was invariant.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.4. Nilotinib improves autophagy flux and reduces A β load in 3-monthold Tg2576 mice · p. 11

    Nilotinib reduced c-Abl phosphorylation in the midbrain from Tg2576 mice, while no changes were observed in basal c-Abl levels.

    “We found that Nilotinib reduced c-Abl phosphorylation in the midbrain from Tg2576 mice (Fig. 5A), while no changes were observed in basal c-Abl levels (Fig. 5A).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.2. DA cell soma alterations in the VTA of 6-month-old Tg2576 mice · p. 9

    There was a strong tendency for reduction in the number of lateral DA neurons at 6 months of age, but it was not significant.

    “As shown in Fig. 3D, we observed a strong tendency for reduction in the number of lateral DA neurons at 6 months of age that was, however, not significant”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.2. DA cell soma alterations in the VTA of 6-month-old Tg2576 mice · p. 9

    At 6 months of age, there was a strong reduction of both area and perimeter in Tg2576 cells in the lateral part of the VTA, while no differences were noticed in the intermediate subregion compared to WT neurons.

    “Even though no differences were noticed in the intermediate subregion compared to WT neurons at 6 months of age, we observed a strong reduction of both area and perimeter in Tg2576 cells in the lateral part of the VTA (Fig. 3C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § 3.5. Nilotinib prevents DA neuron degeneration in Tg2576 mice · p. 11

    Treatment with Nilotinib had no adverse effect on neuronal survival in age-matched WT mice, and the drug was well-tolerated with no apparent differences on animal weight.

    “Additional observations performed on age-matched WT mice showed that treatment with Nilotinib had no adverse effect on neuronal survival (Fig. 6B), and the drug was well-tolerated by the animals despite the long treatment regime, with no apparent differences on animal weight (Supplementary Fig. 4B).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § 4. Discussion · p. 15

    Nilotinib treatment prevents the reduction of DA levels in the hippocampus of Tg2576 mice and the memory deficits related to novel object recognition.

    “Moreover, Nilotinib treatment prevents the reduction of DA levels in the hippocampus of Tg2576 mice and the memory deficits related to novel object recognition.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.

  • It may state two separate claims as one.

    Findingown data
    § 4. Discussion · p. 15

    Treatment of Tg2576 mice with Nilotinib can reduce the activation of c-Abl in DA neurons, thus improving the autophagy activity and Aβ clearance.

    “Importantly, the present data show that treatment of Tg2576 mice with Nilotinib can reduce the activation of c-Abl in DA neurons, thus improving the autophagy activity and A β clearance.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.

  • It may state two separate claims as one.

    Findingreasoning
    § 4. Discussion · p. 15

    Nilotinib prevents the loss as well as the functional and morphological alterations of DA neurons.

    “Closely related to these events, Nilotinib prevents the loss as well as the functional and morphological alterations of DA neurons.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.

  • It may state two separate claims as one.

    Findingown data
    § 4. Discussion · p. 15

    The reduction in soma area and perimeter in 6-month-old Tg2576 mice was only evident in lateral VTA neurons, whereas cells in the intermediate VTA were unaltered.

    “Surprisingly, this effect was only evident in lateral VTA neurons, whereas cells in the intermediate VTA were unaltered.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.

  • It may state two separate claims as one.

    Findingown data
    § 4. Discussion · p. 15

    The increase in phospho-c-Abl appears to be restricted to the midbrain, whereas c-Abl phosphorylation levels and autophagy activity remain unchanged in hippocampus, amygdala, and cortex.

    “Interestingly, the increase in phosho-c-Abl appears to be restricted to the midbrain whereas c-Abl phosphorylation levels and autophagy activity remain unchanged in other brain regions that are particularly relevant to the disease (hippo­ campus, amygdala, and cortex).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.

  • It may state two separate claims as one.

    Findingown data
    § 3.6. Nilotinib prevents memory deficits in 6-month-old Tg2576 mice · p. 13

    During NORT test sessions at 1 and 24 h after training, exposure to a novel object resulted in a significant increase in time spent exploring it for vehicle-treated and Nilotinib-treated WT animals, but not for vehicle-treated Tg2576 mice.

    “During the test sessions, performed 1 and 24 h after training, the exposure to a novel object resulted in a significant increase in the time spent for its exploration for vehicle-treated and Nilotinibtreated WT animals, but not for vehicle-treated Tg2576 mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.
    • Rests on an assumption: The Novel Object Recognition Test measures learning and memory in mice.

  • It may state two separate claims as one.

    Findingown data
    § 4. Discussion · p. 13

    In the Tg2576 mouse model of AD, there is an increased accumulation of autophagosomes in 3-month-old DA neurons, suggesting an alteration in the autophagic mechanism.

    “Here, in the Tg2576 mouse model of AD, we observed an increased accumulation of autophagosomes in 3-month-old DA neurons, suggesting an alteration in the autophagic mechanism.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.

  • Probably not a substantial claim.

    Premisecitation
    § A B S T R A C T · p. 1

    The degeneration of dopaminergic neurons in the VTA could be one of the first events occurring in AD.

    “Recent experimental and clinical studies indicate that the degeneration of the dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA) could be one of the first events occurring in AD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation
    § 1. Introduction · p. 2

    The mesocorticolimbic DA system undergoes profound changes since the early phases of the disease.

    “This evidence supports the notion that the mesocorticolimbic DA system undergoes profound changes since the early phases of the disease”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Martorana and Koch, 2014

  • It may state two separate claims as one.

    Premisecitation
    § 1. Introduction · p. 2

    All attempts to develop Aβ-targeting drugs to reverse deficits in memory and cognition have ended in failure, despite being successful in reducing the Aβ load.

    “all attempts to develop A β -targeting drugs to reverse deficits in memory and cognition have ended in failure, despite being successful in reducing the A β load”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Canter et al., 2016 source
    • cites Huang et al., 2020 source

  • Probably not a substantial claim. The quote only partly states this claim.

    Study design and conductown data
    § 2.7. Stereological analysis · p. 4

    An optical fractionator stereological design was applied for unbiased estimates of TH+ neuron numbers.

    “We applied an optical fractionator stereological design (bilateral count) using the Ste­ reo Investigator System”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    Firing alterations in DA neurons of Tg2576 mice are just beginning at 3 months of age and worsen with age.

    “These data suggest that firing alterations in DA neurons of Tg2576 mice are just beginning at 3 months of age and worsen with age.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.5. Immunohistochemistry and immunofluorescence · p. 4

    Quantification of Aβ expression was conducted blind to the animal's experimental group.

    “Quantification was done on 35 cells per region/mice (n = 4 mice per group) and was conducted blind to the animal ' s experimental group.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    DA neurons in 6-month-old Tg2576 mice have increased excitability and increased functional output during spontaneous pacemaking and in response to current input.

    “These results suggest an increased excitability of DA neurons in 6-month-old Tg2576 mice, and an increased functional output both during spontaneous pace­ making and in response to current input.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cordella et al., 2018 source
    • cites Nobili et al., 2017 source

  • It may state two separate claims as one.

    Premisecitation
    § 1. Introduction · p. 2

    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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cordella et al., 2018 source
    • cites Nobili et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.13. Sample size, randomization and blinding · p. 5

    All randomization was performed by assigning a random number to each animal and using a random number table.

    “All randomization was L. La Barbera et al. performed by assigning a random number to each animal and using a random number table.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    The subtle alterations in Ih- and SK-mediated conductances and the early changes in spontaneous and evoked excitability of Tg2576 DA neurons are all indications of cellular dysfunction.

    “Overall, the subtle alterations in Ih- and SK- mediated conductances and the early changes in the spontaneous and evoked excitability of Tg2576 DA neurons are all indications of cellular dysfunction.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.11. Microdialysis · p. 5

    Data from animals not showing proper placement of microdialysis probes were discarded.

    “Data from animals not showing proper placement were discarded.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cordella et al., 2018 source
    • cites Nobili et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation
    § 2.8.2. Data collection and analysis · p. 5

    Double-membraned autophagosomes were identified according to well-established criteria.

    “double- membraned autophagosomes were identified according to well established criteria”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Eskelinen, 2008 source
    • cites Klionsky et al., 2021 source
    • cites Ylä-Anttila et al., 2009 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.6. Morphological analysis · p. 4

    Twenty-five cells per lateral VTA and twenty-five cells per intermediate VTA per animal were selected randomly for analysis.

    “Overall, twenty-five cells per lateral VTA and twenty-five cells per intermediate VTA per animal were selected randomly for analysis”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation
    § 1. Introduction · p. 2

    Nilotinib has been effectively used to reverse the loss of DA neurons in PD models and to improve cognitive and motor performances via autophagic degradation of Aβ and α-synuclein in models of AD and PD, respectively.

    “Nilotinib has been effectively used to reverse the loss of DA neurons in PD models and to improve cognitive and motor performances via autophagic degrada­ tion of A β and α -synuclein in models of AD and PD, respectively”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hebron et al., 2013a
    • cites Lonskaya et al., 2013b

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data
    § 2.8.1. Post-embedding procedure · p. 5

    Gold particles were not detected when primary antiserum was omitted.

    “Gold particles were not detected when primary antiserum was omitted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.4. Adeno-associated virus (AAV) vector and stereotaxic injection · p. 3

    Data from animals showing misplaced injection site were discarded.

    “Data from animals showing misplaced injection site were discarded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.3. Electrophysiological recordings · p. 3

    Recordings in which membrane access resistance exceeded 25% were discarded.

    “During all experiments, the membrane access resistance was repeatedly monitored and recordings in which it exceeded over 25 % were discarded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data
    § 2.8.1. Post-embedding procedure · p. 5

    When normal serum was substituted for immune serum, sparse and scattered gold particles were observed, but they did not show any specific relationship to subcellular compartments.

    “When normal serum was substituted for immune serum, sparse and scattered gold particles were observed, but they did not show any specific relationship to subcellular compartments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Study design and conductnone given
    § 2.13. Sample size, randomization and blinding · p. 5

    The number of samples in each group and for each experiment was determined based on published studies.

    “The number of samples in each group and for each experiment was determined based on published studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    The after-hyperpolarization current is known to be mediated mainly by SK channels.

    “known to be mediated mainly by Small-Conductance Calcium-Activated K + (SK) channels (Krashia et al., 2019a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Krashia et al., 2019a

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.6. Morphological analysis · p. 4

    Only TH+ neurons identified by a clear nuclear profile were included for morphological analysis.

    “Only TH + neurons identified by a clear nuclear profile were included for analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductnone given
    § 2.13. Sample size, randomization and blinding · p. 6

    All data were collected by researchers blind to the genotype or pharmacological treatment of each animal.

    “All data were collected by researchers that were blind to the genotype or pharmacological treatment of each animal.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 1. Introduction · p. 2

    VTA volume or connectivity alterations are prodromal clinical markers to predict conversion from a healthy state to clinical AD.

    “highlighted the VTA volume or connec­ tivity alterations as prodromal clinical markers to predict conversion from a healthy state to clinical AD”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites D'Amelio et al., 2018a
    • cites Venneri and De Marco, 2020

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data
    § 2.8.1. Post-embedding procedure · p. 5

    The optimal antibody concentration was determined by testing several dilutions, selecting the concentration yielding the lowest background labeling and still immunopositive elements.

    “The optimal concentration of antibodies was sought by testing several dilutions; the concentration yielding the lowest level of background labeling and still immunopositive elements was used to perform the final studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § 2.8.2. Data collection and analysis · p. 5

    Immunogold labeled cytoplasm of neurons were randomly acquired from 12 ultrathin sections per animal.

    “Immunogold labeled cytoplasm of neurons were randomly acquired from 12 ultrathin sections/animal.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data
    § 2.5. Immunohistochemistry and immunofluorescence · p. 4

    The specificity of immunofluorescence labelling was confirmed by omission of primary antibodies and use of normal serum as negative controls.

    “The specificity of the immuno­ fluorescence labelling was confirmed by the omission of primary anti­ bodies and the use of normal serum instead (negative controls).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation
    § 3.1. Increased excitability of DA neurons in the VTA of Tg2576 mice · p. 6

    The majority of afferents onto DA neurons of the VTA-as much as 70% of synaptic inputs-are GABAergic and have a major impact on the activity of DA cells.

    “Given that the majority of afferents onto DA neurons of the VTA -as much as 70 % of synaptic inputs -are GABAergic and have a major impact on the activity of DA cells (Henny et al., 2012; Mathon et al., 2003; White, 1996; Yang et al., 2018)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Henny et al., 2012 source
    • cites Mathon et al., 2003 source
    • cites White, 1996 source

  • It may state two separate claims as one.

    Premisecitation
    § 3.6. Nilotinib prevents memory deficits in 6-month-old Tg2576 mice · p. 11

    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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cordella et al., 2018 source
    • cites Nobili et al., 2017 source

  • It may state two separate claims as one.

    Interpretationown data
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    These data prove an increased activity of the c-Abl tyrosine kinase in the midbrain of 3-month-old Tg2576 mice, that might contribute to the autophagy alterations observed in DA neurons.

    “These data prove an increased activity of the c-Abl tyrosine kinase in the midbrain of 3-month-old Tg2576 mice, that might contribute to the autophagy alterations observed in DA neurons.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    DA neurons have physiological characteristics that make them particularly vulnerable, such as long axons, poorly or completely unmyelinated, that provide massive projections in the target areas.

    “DA neurons have physiological characteristics that make them particularly vulnerable (Chan et al., 2010), such as long axons, poorly or completely unmyelinated, that provide massive projections in the target areas (Braak et al., 2006).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chan et al., 2010
    • cites Braak et al., 2006 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    Phosphorylation of tyrosine residue 412 (p-c-Abl Y412) is important for c-Abl activation and colocalization with degenerating hippocampal neurons in AD subjects.

    “Particularly, we examined the phosphorylation of tyrosine residue 412 (p-c-Abl Y412) that has been shown to be important for c-Abl activation and colocali­ zation with degenerating hippocampal neurons in AD subjects (Jing et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jing et al., 2009 source

  • Probably not a substantial claim.

    Premisecitation
    § 3.2. DA cell soma alterations in the VTA of 6-month-old Tg2576 mice · p. 9

    DA neurons show differences in size along the medio-lateral axis, with the smallest neurons in the intermediate region and the largest in the lateral part.

    “DA neurons are not only functionally heterogeneous, but also show differences in size along the medio-lateral axis, such that the smallest neurons are located within the intermediate region, and the largest neurons in the lateral part (Krashia et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krashia et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    Autophagy impairment has been strongly linked to the degeneration of SNpc DA neurons in PD.

    “In support of the importance of the autophagic process in DA neurons, autophagy impairment has been strongly linked to the degeneration of SNpc DA neurons in PD (Hunn et al., 2019; Isidoro et al., 2009; Sato et al., 2018)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Hunn et al., 2019 source
    • cites Isidoro et al., 2009
    • cites Sato et al., 2018 source

  • It may state two separate claims as one.

    Premisecitation
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    The GFP fluorescence produced by this AAV is sensitive to the acidic and/or proteolytic conditions of the lysosome lumen, while mCherry retains its fluorescence even at acidic pH.

    “The GFP fluorescence produced by this AAV is sensitive to the acidic and/or proteolytic conditions of the lysosome lumen, while mCherry retains its fluorescence even at acidic pH (Matus et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Matus et al., 2014 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 3.4. Nilotinib improves autophagy flux and reduces A β load in 3-monthold Tg2576 mice · p. 9

    Many studies have successfully investigated the therapeutic potential of c-Abl inhibitors.

    “many studies have successfully investigated the therapeutic potential of c-Abl in­ hibitors (Cancino et al., 2011, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cancino et al., 2011, 2008

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    c-Abl is a tyrosine kinase whose increased activity can lead to failure of autophagic protein clearance through the lysosome, resulting in the accumulation of toxic substrates.

    “c-Abl is a tyrosine kinase whose increased activity can lead to failure of auto­ phagic protein clearance through the lysosome, resulting in the accu­ mulation of toxic substrates (Abushouk et al., 2018; Lonskaya et al., 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Abushouk et al., 2018 source
    • cites Lonskaya et al., 2014 source

  • It may state two separate claims as one.

    Interpretationown data
    § 3.5. Nilotinib prevents DA neuron degeneration in Tg2576 mice · p. 11

    Nilotinib succeeds in preventing DA neuron degeneration in Tg2576 mice, similarly to what observed in PD animals.

    “These data prove that, similarly to what observed in PD animals (Hebron et al., 2013a; Karuppagounder et al., 2014), Nilotinib succeeds in preventing DA neuron degeneration also in Tg2576 mice.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Hebron et al., 2013a
    • cites Karuppagounder et al., 2014 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation
    § 3.3. Autophagy alterations in DA neurons in the VTA of Tg2576 mice · p. 9

    LC3 is a cytosolic protein that plays a crucial role in the formation of autophagosomes.

    “LC3 is a cytosolic protein that plays a crucial role in the formation of autophagosomes (Tanida et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tanida et al., 2005 source

  • It may state two separate claims as one.

    Premisecitation
    § 3.6. Nilotinib prevents memory deficits in 6-month-old Tg2576 mice · p. 11

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cordella et al., 2018 source
    • cites Nobili et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 4. Discussion · p. 13

    TEM analysis on post-mortem AD brains revealed the presence of accumulated autophagic vacuoles in dystrophic neurites that are surrounded by neuronal fibrillary tangles.

    “Indeed, TEM analysis on post-mortem AD brains revealed the presence of accumulated auto­ phagic vacuoles in dystrophic neurites that are surrounded by neuronal fibrillary tangles (Nixon et al., 2005; Nixon and Cataldo, 2006), and similar evidence have been also found in AD models (Yang et al., 2011; Yu et al., 2005), although none of these studies have been performed on DA neurons.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nixon et al., 2005 source
    • cites Nixon and Cataldo, 2006

  • It may state two separate claims as one.

    Premisecitation
    § 4. Discussion · p. 15

    c-Abl is an important regulator of the autophagic process and of other pathways that set the choice between survival and cell death.

    “c-Abl is an important regulator of the autophagic process (Abushouk et al., 2018) and of other pathways that set the choice between survival and cell death, thus the observation of an increase in c-Abl phosphorylation in Tg2576 mice is consistent with other studies that identify c-Abl as a pathogenesis mediator in AD (Alvarez et al., 2004; Jing et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Abushouk et al., 2018 source

  • Probably not a substantial claim.

    Premisecitation
    § 4. Discussion · p. 13

    Autophagy is a catabolic process crucial for neuronal survival as it prevents the accumulation of unfolded proteins or damaged organelles, including mitochondria.

    “Autophagy is a catabolic process crucial for neuronal survival as it prevents the accumulation of unfolded proteins or damaged organelles, including mitochondria (Cavallucci et al., 2013a, 2013b; Nixon, 2013; Nobili et al., 2016; Viscomi and D ' Amelio, 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cavallucci et al., 2013a, 2013b
    • cites Nixon, 2013 source
    • cites Nobili et al., 2016

  • It may state two separate claims as one.

    Interpretationcitation
    § 4. Discussion · p. 13

    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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Cordella et al., 2018 source
    • cites Nobili et al., 2017 source
    • Rests on an assumption: The Tg2576 mouse model is a valid model of Alzheimer's disease.

  • It may state two separate claims as one.

    Premisecitation
    § 3.6. Nilotinib prevents memory deficits in 6-month-old Tg2576 mice · p. 11

    DA release in the hippocampus promotes spatial memory, reward-associated memory, novel-object recognition and memory consolidation.

    “DA release in the hippocampus promotes spatial memory, rewardassociated memory, novel-object recognition and memory consolida­ tion (Broussard et al., 2016; Kempadoo et al., 2016; Mamad et al., 2017; McNamara et al., 2014; Rosen et al., 2015; Rossato et al., 2009; Takeuchi et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Broussard et al., 2016 source
    • cites Kempadoo et al., 2016 source
    • cites Mamad et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 4. Discussion · p. 15

    Cell shrinkage is considered one of the main morphological features of apoptosis.

    “Neuronal death in the central nervous system has always been an arduous process to decipher and cell shrinkage is considered one of the main morphological features of apoptosis (Bortner and Cidlowski, 2002).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bortner and Cidlowski, 2002

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § 4. Discussion · p. 13

    Similar evidence of accumulated autophagic vacuoles has been found in AD models.

    “Indeed, TEM analysis on post-mortem AD brains revealed the presence of accumulated auto­ phagic vacuoles in dystrophic neurites that are surrounded by neuronal fibrillary tangles (Nixon et al., 2005; Nixon and Cataldo, 2006), and similar evidence have been also found in AD models (Yang et al., 2011; Yu et al., 2005), although none of these studies have been performed on DA neurons.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yang et al., 2011 source
    • cites Yu et al., 2005

  • It may state two separate claims as one.

    Premisecitation
    § 4. Discussion · p. 15

    At doses lower than the FDA-approved ones for chronic myeloid leukemia, Nilotinib can reduce disease-related biomarkers in phase-2 clinical trials, including amyloid levels and hippocampal volume in AD patients and α-synuclein levels in PD patients.

    “Of note, the positive effect of Nilotinib on DA neuron survival in our AD mice is particularly relevant given that at doses lower than the FDA-approved ones for chronic myeloid leukemia (Deremer et al., 2008; Mahon et al., 2008; Skorski, 2011), the drug can reduce disease-related biomarkers in phase-2 clinical trials -including amyloid levels and hippocampal volume in AD patients and α -synuclein”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pagan et al., 2016, 2019
    • cites Turner et al., 2020 source
70 of 70

  • The paper relies on this without support.

    The causes of the increased vulnerability of VTA DA neurons in AD are unknown.

    “However, the causes of the increased vulnerability of DA neurons in AD are missing.”
    “Despite these clinical advances, however, the causes of the increased vulnerability of VTA DA neurons in AD are still unknown.”

  • The paper relies on this without support.

    What happens precociously to the brain destined to develop AD remains to be elucidated, and this is one reason why effective AD treatments are missing.

    “What happens precociously to the brain destined to develop Alzheimer ' s Disease (AD) still remains to be elucidated and this is one reason why effective AD treatments are missing.”

  • The paper relies on this without support.

    DA neurons have an autonomous pacemaker activity which could contribute to their vulnerability due to high metabolic demand and need of efficient mitochondrial function.

    “In addition, these cells have an autonomous pacemaker activity which could contribute to their vulnerability due to the high metabolic demand and need of efficient mitochondrial func­ tion.”

  • The paper relies on this without support.

    Efficient axonal transport and autophagy mechanisms are needed for the removal of damaged mitochondria and the regeneration of synaptic components.

    “Therefore, efficient axonal transport and autophagy mechanisms are needed for the removal of damaged mitochondria and the regener­ ation of synaptic components.”

  • The paper relies on this without support.

    Any link between autophagy deficits and degeneration of VTA neurons in AD is still missing.

    “yet any link between autophagy deficits and degeneration of VTA neurons in AD is still missing.”

  • The paper relies on this without support.

    DA cells in the VTA are spontaneously active.

    “Since DA cells in the VTA are spontaneously active, we first per­ formed extracellular single-unit recordings from midbrain slices”

  • The paper relies on this without support.

    The Tg2576 mouse model is a valid model of Alzheimer's disease.

    “We report here that the Tg2576 mouse model of AD exhibits early alterations in the function, morphology and autophagic process of VTA dopaminergic neurons.”

  • The paper relies on this without support.

    The Novel Object Recognition Test measures learning and memory in mice.

    “To test different phases of learning and memory in mice, we performed the Novel Object Recognition Test (NORT)”
8 of 8

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?

  • Nilotinib has been shown to prevent degeneration in murine models of AD.

    “Nilotinib, a c-Abl tyrosine kinase inhibitor already approved for the treatment of chronic myeloid leukemia, has been shown to prevent degeneration in murine models of AD [146,147].”

    From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [147]

Citations

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Metadata

Authors
La Barbera, L., Vedele, F., Nobili, A., Krashia, P., Spoleti, E., Latagliata, E. C., Cutuli, D., Cauzzi, E., Marino, R., Viscomi, M. T., Petrosini, L., Puglisi- Allegra, S., Melone, M., Keller, F., Mercuri, N. B., Conti, F., & D’Amelio, M.
Affiliations
  • University of Rome Tor Vergata (IT)
  • Università Campus Bio-Medico (IT)
  • Fondazione Santa Lucia (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • Marche Polytechnic University (IT)
Corresponding author
  • Krashia, Paraskevi
  • D’Amelio, Marcello
ORCID
Venue
Progress in Neurobiology
Publisher
Elsevier BV
Published
2021-07
Volume
202
Pages
102031
ISSN
0301-0082 (ISSN-L)
DOI
10.1016/j.pneurobio.2021.102031
OpenAlex
W3133740594
Semantic Scholar
1f18804308af5e91c7762b8d2a50ccf48db53834
Cited by
98
References
172
Citations by year
2026: 10 · 2025: 24 · 2024: 22 · 2023: 21 · 2022: 17 · 2021: 4
FWCI
10.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Progress in Neurobiology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, cc-by)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
Funders
  • Ministero della Salute
  • Fondazione Roma
  • Alzheimer's Association
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
nilotinib, Alzheimer's disease, dopaminergic neuron loss, ventral tegmental area, c-Abl, autophagy dysfunction, autophagosomes, amyloid-beta, Tg2576 mice, memory function, neurodegeneration, tyrosine kinase inhibition
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Dopamine, Pyrimidines, Ventral Tegmental Area, Mice, Dopaminergic Neurons

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