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

被引:59
作者
La Barbera, Livia [1 ,2 ]
Vedele, Francescangelo [2 ,3 ]
Nobili, Annalisa [1 ,2 ]
Krashia, Paraskevi [1 ,2 ]
Spoleti, Elena [1 ]
Latagliata, Emanuele Claudio [2 ]
Cutuli, Debora [2 ,4 ]
Cauzzi, Emma [1 ,5 ]
Marino, Ramona [1 ]
Viscomi, Maria Teresa [2 ,6 ]
Petrosini, Laura [2 ]
Puglisi-Allegra, Stefano [7 ]
Melone, Marcello [8 ,9 ]
Keller, Flavio [1 ]
Mercuri, Nicola Biagio [2 ,3 ]
Conti, Fiorenzo [8 ,9 ,10 ]
D'Amelio, Marcello [1 ,2 ]
机构
[1] Univ Campus Biomed, Dept Sci & Technol Humans & Environm, Dept Med & Surg, I-00128 Rome, Italy
[2] IRCCS Santa Lucia Fdn, Dept Expt Neurosci, I-00143 Rome, Italy
[3] Univ Roma Tor Vergata, Dept Syst Med, I-00133 Rome, Italy
[4] Sapienza Univ Rome, Dept Psychol, I-00185 Rome, Italy
[5] Univ Milano Bicocca, Sch Med & Surg, Monza, Italy
[6] Univ Cattolica Sacro Cuore, Dept Life Sci & Publ Hlth, Sect Histol & Embryol, I-00168 Rome, Italy
[7] IRCCS Neuromed, I-86077 Pozzilli, Italy
[8] Univ Politecn Marche UNIVPM, Dept Expt & Clin Med, Sect Neurosci & Cell Biol, I-60020 Ancona, Italy
[9] IRCCS Ist Nazl Ricovero & Cura Anziani INRCA, Ctr Neurobiol Aging, I-60020 Ancona, Italy
[10] Univ Politecn Marche, Fdn Mol Med, I-60020 Ancona, Italy
关键词
Ventral Tegmental Area; Autophagy; Midbrain; Tg2576; Tyrosine kinase; VENTRAL TEGMENTAL AREA; OBJECT RECOGNITION MEMORY; ABL TYROSINE KINASE; SK CHANNELS CONTROL; C-ABL; SUBSTANTIA-NIGRA; AMYLOID-BETA; PARKINSONS-DISEASE; I-H; SYNAPTIC PLASTICITY;
D O I
10.1016/j.pneurobio.2021.102031
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 A beta 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.
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页数:21
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