Explore the vast range of titles available.

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder with both genetic and environmental factors contributing to its pathogenesis. While early-onset AD has well-established genetic determinants, the genetic basis for late-onset AD remains less clear. This study investigates a large Italian family with late-onset autosomal dominant AD, identifying a novel rare missense variant in GRIN2C gene associated with the disease, and evaluates the functional impact of this variant. Methods Affected and unaffected members from a Northern Italian family were included. Genomic DNA from family members was extracted and initially screened for pathogenic mutations in APP , PSEN1 , and PSEN2 , and screened for 77 genes associated with neurodegenerative conditions using NeuroX array assay. Exome sequencing was performed on three affected individuals and two healthy relatives. Bioinformatics analyses were conducted. Functional analysis was performed using primary neuronal cultures, and the impact of the variant was assessed through immunocytochemistry and electrophysiology. Results Pathogenic variants were not identified in APP , PSEN1 , or PSEN2 , nor in the 77 genes in NeuroX array assay. Exome Sequencing revealed the c.3215C > T p.(A1072V) variant in GRIN2C gene (NM 000835.6), encoding for the glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 2C (GluN2C). This variant segregated in 6 available AD patients in the family and was absent in 9 healthy relatives. Primary rat hippocampal neurons overexpressing GluN2C A1072V showed an increase in NMDAR-induced currents, suggesting altered glutamatergic transmission. Surface expression assays demonstrated an elevated surface/total ratio of the mutant GluN2C, correlating with the increased NMDAR current. Additionally, immunocytochemistry revealed in neurons expressing the mutant variant a reduced colocalization between the GluN2C subunit and 14-3-3 proteins, which are known to facilitate membrane trafficking of NMDARs. Discussion We identified a rare missense variant in GRIN2C associated with late-onset autosomal dominant Alzheimer's disease. These findings highlight the role of GluN2C-containing NMDARs in glutamatergic signaling and their potential contribution to AD pathogenesis.

The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analyzed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon γ (IFNγ) pathway. Accordingly, we report the capacity of IFNγ to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT. Synopsis To address the unmet need for a cure for RTT, the therapeutic potential of adult Neural Precursor Cells (NPCs) was investigated in vitro on Mecp2 deficient neurons and in vivo in transplanted Mecp2 deficient mice. NPC-secreted molecules rescue typical phenotypes of Mecp2 deficient neurons in culture. NPCs do not require Mecp2 to exert their beneficial effects. Intracerebral transplantation of NPCs prolongs the lifespan of Mecp2 null mice and restores their memory and motor functions. RNA-sequencing studies on transplanted brains have indicated the activation of the IFNγ pathway as a possible mechanism of action. IFNγ treatment of Mecp2 deficient animals and neurons confirms the therapeutic efficacy of the cytokine for RTT. To address the unmet need for a cure for RTT, the therapeutic potential of adult Neural Precursor Cells (NPCs) was investigated in vitro on Mecp2 deficient neurons and in vivo in transplanted Mecp2 deficient mice.

Interest in the function of ataxia-telangiectasia-mutated protein (ATM) is extensively growing as evidenced by preclinical studies that continuously link ATM with new intracellular pathways. Here, we exploited Atm +/− and Atm −/− mice and demonstrate that cognitive defects are rescued by the delivery of the antidepressant Fluoxetine (Fluox). Fluox increases levels of the chloride intruder NKCC1 exclusively at hippocampal level suggesting an ATM context-specificity. A deeper investigation of synaptic composition unveils increased Gluk-1 and Gluk-5 subunit-containing kainate receptors (KARs) levels in the hippocampus, but not in the cortex, of Atm +/− and Atm −/− mice. Analysis of postsynaptic fractions and confocal studies indicates that KARs are presynaptic while in vitro and ex vivo electrophysiology that are fully active. These changes are (i) linked to KCC2 activity, as the KCC2 blockade in Atm +/− developing neurons results in reduced KARs levels and (ii) developmental regulated. Indeed, the pharmacological inhibition of ATM kinase in adults produces different changes as identified by RNA-seq investigation. Our data display how ATM affects both inhibitory and excitatory neurotransmission, extending its role to a variety of neurological and psychiatric disorders.

Impairment of the GABAergic system has been reported in epilepsy, autism, attention deficit hyperactivity disorder, and schizophrenia. We recently demonstrated that ataxia telangiectasia mutated (ATM) directly shapes the development of the GABAergic system. Here, we show for the first time to our knowledge how the abnormal expression of ATM affects the pathological condition of autism. We exploited 2 different animal models of autism, the methyl CpG binding protein 2-null (Mecp2y/-) mouse model of Rett syndrome and mice prenatally exposed to valproic acid, and found increased ATM levels. Accordingly, treatment with the specific ATM kinase inhibitor KU55933 (KU) normalized molecular, functional, and behavioral defects in these mouse models, such as (a) delayed GABAergic development, (b) hippocampal hyperexcitability, (c) low cognitive performances, and (d) social impairments. Mechanistically, we demonstrate that KU administration to WT hippocampal neurons leads to (a) higher early growth response 4 activity on Kcc2b promoter, (b) increased expression of Mecp2, and (c) potentiated GABA transmission. These results provide evidence and molecular substrates for the pharmacological development of ATM inhibition in autism spectrum disorders.

Given its potential role in supporting cognitive resilience, PLA2G4E has emerged as a compelling therapeutic target in the context of Alzheimer’s disease (AD). However, its physiological functions in the central nervous system remain largely unexplored. In this study, we demonstrate that Pla2g4e expression peaks during early postnatal brain development, coinciding with the rapid formation of synapses. Loss-of-function experiments in primary neuronal cultures revealed that Pla2g4e expression is essential for proper dendritic development and neuronal maturation. In constitutive Pla2g4e knockout mice, we observed significant disruptions in the developmental profiles of cortical synaptic plasticity markers, accompanied by impairments in memory-related behaviors. Notably, the adeno-associated virus–mediated overexpression of PLA2G4E rescued memory deficits, highlighting its functional relevance in cognitive processes. Furthermore, selective deletion of Pla2g4e in excitatory neurons of the adult brain resulted in moderate memory impairments in aged animals, suggesting an ongoing role in synaptic maintenance. Together, these findings establish PLA2G4E as a key regulator of dendritic architecture, synaptic function, and cognitive performance, and highlight its potential as a gene therapy target for neurodegenerative diseases characterized by synaptic dysfunction.

The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from an NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analysed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon γ (IFNγ) pathway. Accordingly, we report the capacity of IFNγ to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT.Competing Interest StatementThe authors have declared no competing interest.