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Introduction: A predominant molecular component analyzed in the study of neurodegenerative diseases is the presence of the Tau-GSK3beta complex and its association with protein aggregation into the cell. Several evidences show that GSK3beta has an important role in abnormal pattern of the phosphorylation of Tau. However, the molecular events that are governing this complex are unknown.Aim: To determine the effect of 17 beta-estradiol treatment on the expression and association of Tau hyperphosphorylation responsible kinases.Methods: 17 beta-estradiol treatments were realized in the hippocampus of ovariectomized adult wistar rats and in hippocampal primary cultures treated with beta-amiloid. Protein complex association was assessed by co-immunoprecipitation, toxicity assay by LDH release and cell morphologic changes by confocal microscopy.Results: Our results show that 17beta-estradiol produced dissociation of macromolecular complexes like Tau/GSK3beta, Tau /GluR2/3, Tau/FAK, and Tau/Fyn in hippocampus of adult rat. In addition the expression of GSK3beta-ptyr was decreased by the hormonal treatment and this one regulated the defosforilation of Tau in an excitotoxicity model by beta-amiloid.Conclusions: It suggests new targets that will contribute to neuroprotection and neuronal plasticity studies mediated by the estrogen. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is the second most prevalent type of early-onset dementia and up to 40% of cases are familial forms. One of the genes mutated in patients is CHMP2B , which encodes a protein found in a complex important for maturation of late endosomes, an essential process for recycling membrane proteins through the endolysosomal system. Here, we have generated a CHMP2B -mutated human embryonic stem cell line using genome editing with the purpose to create a human in vitro FTD disease model. To date, most studies have focused on neuronal alterations; however, we present a new co-culture system in which neurons and astrocytes are independently generated from human embryonic stem cells and combined in co-cultures. With this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and a neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Tissue clearing is commonly used for whole-brain imaging but seldom used for brain slices. Here, we present a simple protocol to slice, immunostain, and clear sections of adult rat brains for subsequent high-resolution confocal imaging. The protocol does not require toxic reagents or specialized equipment. We also provide instructions for culturing of rat brain slices free floating on permeable culture inserts, maintained in regular CO 2 incubators, and handled only at media change., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation in vivo . Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the brain. We hypothesize that resolving the subcellular location of t-LTP and t-LTD mechanisms that are regulated by distinct neuromodulator systems will be essential to reach a more cohesive understanding of synaptic plasticity in memory formation.

Timing-dependent LTP (t-LTP) is a physiologically relevant type of synaptic plasticity that results from repeated sequential firing of action potentials (APs) in pre- and postsynaptic neurons. t-LTP can be observed in vivo and is proposed to be a cellular correlate of memory formation. While brain-derived neurotrophic factor (BDNF) is essential to high-frequency stimulation-induced LTP in many brain areas, the role of BDNF in t-LTP is largely unknown. Here, we demonstrate a striking change in the expression mechanism of t-LTP in CA1 of the hippocampus following two distinct modes of synaptic activation. Single postsynaptic APs paired with presynaptic stimulation activated a BDNF-independent canonical t-LTP. In contrast, a theta burst of postsynaptic APs preceded by presynaptic stimulation elicited BDNF-dependent postsynaptic t-LTP that relied on postsynaptic BDNF secretion. This suggests that BDNF release during burst-like patterns of activity typically observed in vivo may play a crucial role during memory formation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Several studies have linked estrogens with sphingosine kinase (SphK) activity, enzyme responsible of sphingosine-1-phosphate synthesis (S-1P), however their possible interaction in the nervous system is not documented yet. In the present study, we developed a glutamate toxicity model in SH-SY5Y cells to evaluate the possible effect of the inhibition of SphK activity on the protective capability of 17β-estradiol (E2). Glutamate induced cytoskeletal actin changes associated to cytotoxic stress, significant increase of apoptotic-like nuclear fragmentation, Tau hyperphosphorylation and increase of p25/p35 cleavage. These effects were prevented by E2 pre-treatment during 24 h. Although the inhibition of SphK did not block this protective effect, significantly increased Tau hyperphosphorylation by glutamate, in a way that was not reverted by E2. Our results suggest that the decrease of glutamate-induced Tau hyperphosphorylation by 17β-estradiol requires SphK.