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Early and progressive dysfunctions of the dopaminergic system from the Ventral Tegmental Area (VTA) have been described in Alzheimer's Disease (AD). During the long pre-symptomatic phase, alterations in the function of Parvalbumin interneurons (PV-INs) are also observed, resulting in cortical hyperexcitability represented by subclinical epilepsy and aberrant gamma-oscillations. However, it is unknown whether the dopaminergic deficits contribute to brain hyperexcitability in AD. Here, using the Tg2576 mouse model of AD, we prove that reduced hippocampal dopaminergic innervation, due to VTA dopamine neuron degeneration, impairs PV-IN firing and gamma-waves, weakens the inhibition of pyramidal neurons and induces hippocampal hyperexcitability via lower D2-receptor-mediated activation of the CREB-pathway. These alterations coincide with reduced PV-IN numbers and Perineuronal Net density. Importantly, L-DOPA and the selective D2-receptor agonist quinpirole rescue p-CREB levels and improve the PV-IN-mediated inhibition, thus reducing hyperexcitability. Moreover, similarly to quinpirole, sumanirole - another D2-receptor agonist and a known anticonvulsant - not only increases p-CREB levels in PV-INs but also restores gamma-oscillations in Tg2576 mice. Conversely, blocking the dopaminergic transmission with sulpiride (a D2-like receptor antagonist) in WT mice reduces p-CREB levels in PV-INs, mimicking what occurs in Tg2576. Overall, these findings support the hypothesis that the VTA dopaminergic system integrity plays a key role in hippocampal PV-IN function and survival, disclosing a relevant contribution of the reduced dopaminergic tone to aberrant gamma-waves, hippocampal hyperexcitability and epileptiform activity in early AD., (© 2024. The Author(s).)

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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alzheimer disease (AD) is a neurodegenerative disorder for which no approved medication exists. AD is characterized by worsening cognitive and non-cognitive symptoms, and research in the AD field strives to identify very precocious brain alterations leading to an irreversible condition. Recently it has been demonstrated that several early AD symptoms are paralleled with degeneration of neurons producing dopamine (DA), a neurotransmitter involved in the regulation of cognitive and non-cognitive functions. Actually, we found that ventral tegmental area (VTA) DA neurons degenerate early in a validated AD mouse model (Tg2576). Here, we summarize new data showing how macroautophagy/autophagy impairment - due to enhanced activity of the ABL/c-Abl kinase - might cause the DA neuron loss. We also proved that nilotinib, an ABL inhibitor, restores autophagy flux, thus preventing VTA neurodegeneration. Most notably, from a clinical point of view, nilotinib, by preventing DA neuronal loss, preserves DA outflow in VTA-projecting areas, improving Tg2576 behavioral phenotypes. Our findings shed light on the mechanism involved in DA neurodegeneration, revealing that autophagy represents a viable therapeutic target in early AD.

Alzheimer's disease (AD) is a progressive neurological disorder characterized by several cognitive and non-cognitive symptoms, with episodic memory being the earliest and most prominently impaired cognitive function. Dopaminergic signals are required for encoding hippocampal memory for new events and the ventral tegmental area (VTA), together with the locus coeruleus, are the primary sources of dopamine acting on dopaminergic receptors in the hippocampus. With this in mind, a recent study on a validated mouse model of AD highlighted on the hippocampal dysfunction and its correlation with an early degeneration of dopaminergic neurons in the VTA. In this issue, De Marco and Venneri test the hypothesis that the volume of the VTA nucleus in humans might be associated with cognitive features of AD.

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.

The presence of α-synuclein (α-syn) in Lewy bodies and Lewy neurites is an important characteristic of the neurodegenerative processes of substantia nigra pars compacta (SNpc) dopaminergic (DAergic) neurons in Parkinson's disease (PD) and other synucleinopathies. Here we report that Berlin-Druckrey rats carrying a spontaneous mutation in the 3' untranslated region of α-syn mRNA (m/m rats) display a marked accumulation of α-syn in the mesencephalic area, striatum and frontal cortex, accompanied to severe dysfunctions in the dorsolateral striatum. Despite a small reduction in the number of SNpc and ventral tegmental area DAergic cells, the surviving dopaminergic neurons of the m/m rats do not show clear-cut alterations of the spontaneous and evoked firing activity, DA responses and somatic amphetamine-induced firing inhibition. Interestingly, mutant DAergic neurons display diminished whole-cell Ih conductance and a reduced frequency of spontaneous excitatory synaptic currents. By contrast, m/m rats show a severe impairment of DA and glutamate release in the dorsolateral striatum, as revealed by amperometric measure of DA currents and by electrophysiological recordings of glutamatergic synaptic events in striatal medium spiny neurons. These functional impairments are paralleled by a decreased expression of the DA transporter and VGluT1 proteins in the same area. Thus, together with α-syn overload in the mesencephalic region, striatum and frontal cortex, the main functional alterations occur in the DAergic and glutamatergic terminals in the dorsal striatum of the m/m rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We studied the properties of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) in mice expressing the enhanced green fluorescent protein (eGFP) under the control of the tyrosine hydroxylase promoter (TH-GFP). By using a practical map of cell positioning in distinct SNpc and VTA subregions in horizontal midbrain slices we saw that the spontaneous firing, membrane properties, cell body size and magnitude of the hyperpolarization-activated current (I h ) in TH-GFP-positive neurons (TH-GFP + ) vary significantly among subregions, following a mediolateral gradient. Block of I h with Zd7288 inhibited firing in the most lateral subregions, but had little effect in the intermediate/medial VTA. In addition, TH-GFP + cells were excited by Met 5 -Enkephalin. Extracellular recordings from a large neuron number showed that all TH-GFP + cells were inhibited by dopamine, suggesting that this is a reliable approach for identifying dopaminergic neurons in vitro. Simultaneous recordings from dopamine-sensitive and dopamine-insensitive neurons showed that dopamine-insensitive cells (putative non-dopaminergic neurons) are unaffected by Zd7288 but inhibited by Met 5 -Enkephalin. Under patch-clamp, dopamine generated a quantitatively similar outward current in most TH-GFP + neurons, although medial VTA cells showed reduced dopamine sensitivity. Pargyline prolonged the dopamine current, whereas cocaine enhanced dopamine-mediated responses in both the SNpc and the VTA. Our work provides new insights into the variability in mouse midbrain dopaminergic neurons along the medial-lateral axis and points to the necessity of a combination of different electrophysiological and pharmacological approaches for reliably identifying these cells to distinguish them from non-dopaminergic neurons in the midbrain., (© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Dopamine neurons in the substantia nigra pars compacta regulate not only motor but also cognitive functions. NMDA receptors play a crucial role in modulating the activity of these cells. Considering that the amino-acid D-Aspartate has been recently shown to be an endogenous NMDA receptor agonist, the aim of the present study was to examine the effects of D-Aspartate on the functional properties of nigral dopamine neurons. We compared the electrophysiological actions of D-Aspartate in control and D-aspartate oxidase gene (Ddo(-/-)) knock-out mice that show a concomitant increase in brain D-Aspartate levels, improved synaptic plasticity and cognition. Finally, we analyzed the effects of L-Aspartate, a known dopamine neuron endogenous agonist in control and Ddo(-/-) mice. We show that D- and L-Aspartate excite dopamine neurons by activating NMDA, AMPA and metabotropic glutamate receptors. Ddo deletion did not alter the intrinsic properties or dopamine sensitivity of dopamine neurons. However, NMDA-induced currents were enhanced and membrane levels of the NMDA receptor GluN1 and GluN2A subunits were increased. Inhibition of excitatory amino-acid transporters caused a marked potentiation of D-Aspartate, but not L-Aspartate currents, in Ddo(-/-) neurons. This is the first study to show the actions of D-Aspartate on midbrain dopamine neurons, activating not only NMDA but also non-NMDA receptors. Our data suggest that dopamine neurons, under conditions of high D-Aspartate levels, build a protective uptake mechanism to compensate for increased NMDA receptor numbers and cell hyper-excitation, which could prevent the consequent hyper-dopaminergia in target zones that can lead to neuronal degeneration, motor and cognitive alterations., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) occur in nearly all patients with Alzheimer's Disease (AD). Most frequently they appear since the mild cognitive impairment (MCI) stage preceding clinical AD, and have a prognostic importance. Unfortunately, these symptoms also worsen the daily functioning of patients, increase caregiver stress and accelerate the disease progression from MCI to AD. Apathy and depression are the most common of these NPS, and much attention has been given in recent years to understand the biological mechanisms related to their appearance in AD. Although for many decades these symptoms have been known to be related to abnormalities of the dopaminergic ventral tegmental area (VTA), a direct association between deficits in the VTA and NPS in AD has never been investigated. Fortunately, this scenario is changing since recent studies using preclinical models of AD, and clinical studies in MCI and AD patients demonstrated a number of functional, structural and metabolic alterations affecting the VTA dopaminergic neurons and theirmesocorticolimbic targets. These findings appear early, since theMCI stage, and seem to correlate with the appearance of NPS. Here, we provide an overview of the recent evidence directly linking the dopaminergic VTA with NPS in AD and propose a setting in which the precocious identification of dopaminergic deficits can be a helpful biomarker for early diagnosis. In this scenario, treatments of patients with dopaminergic drugs might slow down the disease progression and delay the impairment of daily living activities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mammalian brain cortical functions, from executive and motor functioning to memory and emotional regulation, are strictly regulated by subcortical projections. These projections terminate in cortical areas that are continuously influenced by released neurotransmitters and neuromodulators. Among the subcortical structures, the dopaminergic midbrain plays a pivotal role in tuning cortical functions that commonly result altered in many neurological and psychiatric disorders. Incidentally, extensive neuropathological observations support a strong link between structural alterations of the dopaminergic midbrain and significant behavioural symptomatology observed in patients suffering from Alzheimer ’s disease(AD). Here, we will review recent progress on the involvement of the dopaminergic system in the pathophysiology of AD as well as the current therapeutic strategies targeting this system. [ABSTRACT FROM AUTHOR]