Upregulation of Ca2+-binding proteins contributes to VTA dopamine neuron survival in the early phases of Alzheimer’s disease in Tg2576 mice

Springer Science and Business Media LLC - 2022
Livia La Barbera1,2, Annalisa Nobili1,2, Emma Cauzzi2,3, Ilaria Paoletti1, Mauro Federici2, Luana Saba1,2, Cecilia Giacomet3, Ramona Marino1, Paraskevi Krashia2,4, Marcello Melone5,6, Flavio Keller1, Nicola Biagio Mercuri2,3, Maria Teresa Viscomi7,8, Fiorenzo Conti5,6,9, Marcello D’Amelio1,2
1Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
2Department of Experimental Neurosciences, IRCCS Santa Lucia Foundation, Rome, Italy
3Department of Systems Medicine, “University of Rome Tor Vergata”, Rome, Italy
4Department of Sciences and Technologies for Humans and Environment, Università Campus Bio-Medico di Roma, Rome, Italy
5Center for Neurobiology of Aging, IRCCS Istituto Nazionale Ricovero e Cura Anziani (INRCA), Ancona, Italy
6Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica delle Marche (UNIVPM), Ancona, Italy
7Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
8Department of Life Science and Public Health; Section of Histology and Embryology, Università Cattolica del Sacro Cuore, Rome, Italy
9Foundation for Molecular Medicine, Università Politecnica delle Marche, Ancona, Italy

Tóm tắt

Recent clinical and experimental studies have highlighted the involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons for the early pathogenesis of Alzheimer’s Disease (AD). We have previously described a progressive and selective degeneration of these neurons in the Tg2576 mouse model of AD, long before amyloid-beta plaque formation. The degenerative process in DA neurons is associated with an autophagy flux impairment, whose rescue can prevent neuronal loss. Impairments in autophagy can be the basis for accumulation of damaged mitochondria, leading to disturbance in calcium (Ca2+) homeostasis, and to functional and structural deterioration of DA neurons. In Tg2576 mice, we performed amperometric recordings of DA levels and analysis of dopaminergic fibers in the Nucleus Accumbens – a major component of the ventral striatum precociously affected in AD patients – together with retrograde tracing, to identify the most vulnerable DA neuron subpopulations in the VTA. Then, we focused on these neurons to analyze mitochondrial integrity and Apoptosis-inducing factor (AIF) localization by electron and confocal microscopy, respectively. Stereological cell count was also used to evaluate degeneration of DA neuron subpopulations containing the Ca2+-binding proteins Calbindin-D28K and Calretinin. The expression levels for these proteins were analyzed by western blot and confocal microscopy. Lastly, using electrophysiology and microfluorometry we analyzed VTA DA neuron intrinsic properties and cytosolic free Ca2+ levels. We found a progressive degeneration of mesolimbic DA neurons projecting to the ventral striatum, located in the paranigral nucleus and parabrachial pigmented subnucleus of the VTA. At the onset of degeneration (3 months of age), the vulnerable DA neurons in the Tg2576 accumulate damaged mitochondria, while AIF translocates from the mitochondria to the nucleus. Although we describe an age-dependent loss of the DA neurons expressing Calbindin-D28K or Calretinin, we observed that the remaining cells upregulate the levels of Ca2+-binding proteins, and the free cytosolic levels of Ca2+ in these neurons are significantly decreased. Coherently, TUNEL-stained Tg2576 DA neurons express lower levels of Calbindin-D28K when compared with non-apoptotic cells. Overall, our results suggest that the overexpression of Ca2+-binding proteins in VTA DA neurons might be an attempt of cells to survive by increasing their ability to buffer free Ca2+. Exploring strategies to overexpress Ca2+-binding proteins could be fundamental to reduce neuronal suffering and improve cognitive and non-cognitive functions in AD.

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