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

Barbera, Livia La; 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

doi:10.1016/j.pneurobio.2021.102031

Cited by 59 publications

(78 citation statements)

References 149 publications

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“…The neurobiological substrate of this increased risk is likely related to a release of connectivity between VTA and DMN. Our findings are consistent with recent research that contributed to shed light on the strategic role of dopamine in AD pathophysiology [27,66,[69][70].…”

Section: Discussionsupporting

confidence: 93%

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Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer’s Disease: Implications for Treatment

Serra

D’Amelio

Esposito

et al. 2021

JAD

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Background: Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer’s disease (AD). Objective: In this study, we longitudinally investigated by resting-state fMRI (RS-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. Methods: A cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and RS-fMRI to assess VTA connectivity at baseline and at follow-up. Results: At 24-month follow-up, 16 out of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-converters compared to non-converters remained substantially unchanged at 24-month follow-up. Conclusion: This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression.

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Section: Discussionsupporting

confidence: 93%

“…Notably, the dysfunction of dopaminergic transmission has been hypothesized as a new player in the pathophysiology of AD [21][22][23][24][25][26][27][28][29][68][69][70]. Post mortem studies revealed marked loss of DA receptors in the temporal and frontal lobes of AD brains [21,23,24], regions classically involved in cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer’s Disease: Implications for Treatment

Serra

D’Amelio

Esposito

et al. 2021

JAD

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“…Recently, c-Abl has been shown to be involved in autophagy. Chronic treatment with nilotinib, a clinically validated c-Abl inhibitor, improves autophagy, reduces Aβ levels, and prevents neurodegeneration in an Alzheimer’s mouse model ( La Barbera et al, 2021 ). In Parkinson’s, nilotinib induces cellular clearance of α-synuclein, via autophagic degradation, and protects the dopaminergic neurons, improving locomotor function in mouse models of this disease ( Hebron et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease

Marín

Dulcey

Campos

et al. 2022

Front. Cell Dev. Biol.

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Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lowers sphingomyelin accumulation in NPA patient fibroblasts and NPA neuronal models and 3) chronic treatment with nilotinib and neurotinib, two c-Abl inhibitors with differences in blood-brain barrier penetrance and target binding mode, show further benefits. While nilotinib treatment reduces neuronal death in the cerebellum and improves locomotor functions, neurotinib decreases glial activation, neuronal disorganization, and loss in hippocampus and cortex, as well as the cognitive decline of NPA mice. Our results support the participation of c-Abl signaling in NPA neurodegeneration and autophagy-lysosomal alterations, supporting the potential use of c-Abl inhibitors for the clinical treatment of NPA patients.

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“…AD, as a common progressively neurodegenerative disorder, endangers the memory and cognitive abilities of people around the world [34,35]. As the universal animal model of AD, APP/PS1 mice stably display mouse/human APP located in neurons and mutant human PS1 and there are senile plaque deposits in the brain at the age of 6 months, and memory ability decline with age [36].…”

Section: Discussionmentioning

confidence: 99%

Astragalin Ameliorates Cognitive Dysfunction Through Inhibiting PI3K/Akt-MTOR-Mediated Autophagic Flow in Hippocampal Neurons of APP/PS1 Mice

Yang

Zhang

Wang

et al. 2022

Preprint

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Astragalin (AST), a natural small molecule flavonoid, can exert anti-oxidant, anti-inflammatory and anti-cancer impacts by regulating autophagy. However, the potential mechanism of the neuroprotective effect of AST on neurological disorders such as Alzheimer’s disease (AD) is still not clear. In the present study, we firstly screened AST for the treatment of AD from the ingredients of Chinese medicines such as Acori tataninowii Rhizoma, Eucommiae Cortex, Paeoniae Radix Alba through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) database. And then we found that AST could improve the cognitive abilities of APP/PS1 mice by Step-down passive avoidance (SDA) and Morris Water Maze (MWM) Test. Further, we identified that AST diminished Aβ plaques deposition in the brains of APP/PS1 mice and Aβ as well as Aβ42 levels in the serum of APP/PS1 mice. Next, microtubule-associated protein 1 light chain 3B (LC3B), p62, Beclin-1, ATG5, ATG12, LAMP-1 were observed to be co-expressed with NeuN in the hippocampus of APP/PS1 mice by immunofluorescent multiplex staining, while AST was able to activate autophagy and maintain autophagic flow in hippocampal neurons of APP/PS1 mice by western blot (WB) analysis. Finally, AST reduced the expressions of p-PI3K, p-Akt, p-mTOR by WB analysis. Taken together, we confirmed that AST may play key neuroprotective effects on APP/PS1 mice by inhibiting the PI3K/Akt-mTOR signaling pathway to activate autophagy and keep autophagic flow smooth.

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

Cited by 59 publications

References 149 publications

Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer’s Disease: Implications for Treatment

Ventral Tegmental Area Disconnection Contributes Two Years Early to Correctly Classify Patients Converted to Alzheimer’s Disease: Implications for Treatment

c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease

Astragalin Ameliorates Cognitive Dysfunction Through Inhibiting PI3K/Akt-MTOR-Mediated Autophagic Flow in Hippocampal Neurons of APP/PS1 Mice

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