Transcranial alternating current stimulation (tACS) at gamma frequency: an up-and-coming tool to modify the progression of Alzheimer's Disease.

The last decades have witnessed huge efforts devoted to deciphering the pathological mechanisms underlying Alzheimer's Disease (AD) and to testing new drugs, with the recent FDA approval of two anti-amyloid monoclonal antibodies for AD treatment. Beyond these drug-based experimentations, a number of pre-clinical and clinical trials are exploring the benefits of alternative treatments, such as non-invasive stimulation techniques on AD neuropathology and symptoms. Among the different non-invasive brain stimulation approaches, transcranial alternating current stimulation (tACS) is gaining particular attention due to its ability to externally control gamma oscillations.

Dopamine neuron degeneration in the Ventral Tegmental Area causes hippocampal hyperexcitability in experimental Alzheimer's Disease.

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.

The role of dopamine in NLRP3 inflammasome inhibition: Implications for neurodegenerative diseases.

In the Central Nervous System (CNS), neuroinflammation orchestrated by microglia and astrocytes is an innate immune response to counteract stressful and dangerous insults. One of the most important and best characterized players in the neuroinflammatory response is the NLRP3 inflammasome, a multiproteic complex composed by NOD-like receptor family Pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and pro-caspase-1. Different stimuli mediate NLRP3 activation, resulting in the NLRP3 inflammasome assembly and the pro-inflammatory cytokine (IL-1β and IL-18) maturation and secretion.

Chemogenetic rectification of the inhibitory tone onto hippocampal neurons reverts autistic-like traits and normalizes local expression of estrogen receptors in the Ambra1+/- mouse model of female autism.

Female, but not male, mice with haploinsufficiency for the proautophagic Ambra1 gene show an autistic-like phenotype associated with hippocampal circuits dysfunctions which include loss of parvalbuminergic interneurons (PV-IN), decrease in the inhibition/excitation ratio, and abundance of immature dendritic spines on CA1 pyramidal neurons. Given the paucity of data relating to female autism, we exploit the Ambra1 female model to investigate whether rectifying the inhibitory input onto hippocampal principal neurons (PN) rescues their ASD-like phenotype at both the systems and circuits level. Moreover, being the autistic phenotype exclusively observed in the female mice, we control the effect of the mutation and treatment on hippocampal expression of estrogen receptors (ER).

Upregulation of Ca-binding proteins contributes to VTA dopamine neuron survival in the early phases of Alzheimer's disease in Tg2576 mice.

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.

The VTA dopaminergic system as diagnostic and therapeutical target for Alzheimer's disease.

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.

Early derailment of firing properties in CA1 pyramidal cells of the ventral hippocampus in an Alzheimer's disease mouse model.

Gradual decline in cognitive and non-cognitive functions are considered clinical hallmarks of Alzheimer's Disease (AD). Post-mortem autoptic analysis shows the presence of amyloid β deposits, neuroinflammation and severe brain atrophy. However, brain circuit alterations and cellular derailments, assessed in very early stages of AD, still remain elusive.

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

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.

Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer's disease models.

Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH26-230 fragment (i.

Cisd2: a promising new target in Alzheimer's disease.

The CISD2 gene encodes the CDGSH iron-sulfur domain-containing protein 2. Cisd2 is involved in mammalian lifespan control, the unfolded protein response, Ca buffering, and autophagy regulation. It has been demonstrated previously that Cisd2 deficiency causes an accelerated ageing phenotype characterised by the accumulation of damaged mitochondria, while Cisd2 overexpression leads to mitochondrial protection against typical age-associated alterations.

Hippocampal epileptogenesis in autoimmune encephalitis.

Objective: Autoantibody-mediated forms of encephalitis (AE) include neurological disorders characterized by subacute memory loss, movement disorders, and, often, frequent, focal epileptic seizures. Yet, the electrophysiological effects of these autoantibodies on neuronal function have received little attention. In this study, we assessed the effects of CSF containing autoantibodies on intrinsic and extrinsic properties of hippocampal neurons, to define their epileptogenic potential.

Author Correction: Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease.

Neuroinflammation is one of the hallmarks of Parkinson's disease (PD) and may contribute to midbrain dopamine (DA) neuron degeneration. Recent studies link chronic inflammation with failure to resolve early inflammation, a process operated by specialized pro-resolving mediators, including resolvins. However, the effects of stimulating the resolution of inflammation in PD - to modulate disease progression - still remain unexplored.

Neurodevelopmental Disorders: Functional Role of Ambra1 in Autism and Schizophrenia.

The activating molecule in Beclin-1-regulated autophagy (Ambra1) is a highly intrinsically disordered protein best known for its role as a mediator in autophagy, by favoring the formation of autophagosomes. Additional studies have revealed that Ambra1 is able to coordinate cell responses to stress conditions such as starvation, and it actively participates in cell proliferation, cytoskeletal modification, apoptosis, mitochondria removal, and cell cycle downregulation. All these functions highlight the importance of Ambra1 in crucial physiological events, including metabolism, cell death, and cell division.

Dopamine loss alters the hippocampus-nucleus accumbens synaptic transmission in the Tg2576 mouse model of Alzheimer's disease.

The functional loop involving the ventral tegmental area (VTA), dorsal hippocampus and nucleus accumbens (NAc) plays a pivotal role in the formation of spatial memory and persistent memory traces. In particular, the dopaminergic innervation from the VTA to the hippocampus is critical for hippocampal-related memory function and alterations in the midbrain dopaminergic system are frequently reported in Alzheimer's disease (AD), contributing to age-related decline in memory and non-cognitive functions. However, much less is known about the hippocampus-NAc connectivity in AD.

Ambra1 Shapes Hippocampal Inhibition/Excitation Balance: Role in Neurodevelopmental Disorders.

Imbalances between excitatory and inhibitory synaptic transmission cause brain network dysfunction and are central to the pathogenesis of neurodevelopmental disorders. Parvalbumin interneurons are highly implicated in this imbalance. Here, we probed the social behavior and hippocampal function of mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene crucial for brain development.

Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease.

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).

On the properties of identified dopaminergic neurons in the mouse substantia nigra and ventral tegmental area.

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 ) in TH-GFP-positive neurons (TH-GFP ) vary significantly among subregions, following a mediolateral gradient. Block of I with Zd7288 inhibited firing in the most lateral subregions, but had little effect in the intermediate/medial VTA.

The long activations of α2 glycine channels can be described by a mechanism with reaction intermediates ("flip").

The α2 glycine receptor (GlyR) subunit, abundant in embryonic neurons, is replaced by α1 in the adult nervous system. The single-channel activity of homomeric α2 channels differs from that of α1-containing GlyRs, as even at the lowest glycine concentration (20 µM), openings occurred in long (>300-ms) groups with high open probability (P(open); 0.96; cell-attached recordings, HEK-expressed channels).

Human α3β4 neuronal nicotinic receptors show different stoichiometry if they are expressed in Xenopus oocytes or mammalian HEK293 cells.

Background: The neuronal nicotinic receptors that mediate excitatory transmission in autonomic ganglia are thought to be formed mainly by the α3 and β4 subunits. Expressing this composition in oocytes fails to reproduce the properties of ganglionic receptors, which may also incorporate the α5 and/or β2 subunits. We compared the properties of human α3β4 neuronal nicotinic receptors expressed in Human embryonic kidney cells (HEK293) and in Xenopus oocytes, to examine the effect of the expression system and α:β subunit ratio.

Agonist and blocking actions of choline and tetramethylammonium on human muscle acetylcholine receptors.

Choline has been used widely as an agonist for the investigation of gain-of-function mutants of the nicotinic acetylcholine receptor. It is useful because it behaves like a partial agonist. The efficacy of choline is difficult to measure because choline blocks the channel at concentrations about four times lower than those that activate it.

Incorporation of the beta3 subunit has a dominant-negative effect on the function of recombinant central-type neuronal nicotinic receptors.

The beta3 neuronal nicotinic subunit is localized in dopaminergic areas of the central nervous system, in which many other neuronal nicotinic subunits are expressed. So far, beta3 has only been shown to form functional receptors when expressed together with the alpha3 and beta4 subunits. We have systematically tested in Xenopus laevis oocytes the effects of coexpressing human beta3 with every pairwise functional combination of neuronal nicotinic subunits likely to be relevant to the central nervous system.