A Screen of Plant-Based Natural Products Revealed That Quercetin Prevents Pyroglutamylated Amyloid-β (Aβ3(pE)-42) Uptake in Astrocytes As Well As Resulting Astrogliosis and Synaptic Dysfunction.

Two connected histopathological hallmarks of Alzheimer's disease (AD) are chronic neuroinflammation and synaptic dysfunction. The accumulation of the most prevalent posttranslationally modified form of Aβ1-42, pyroglutamylated amyloid-β (Aβ3(pE)-42) in astrocytes is directly linked to glial activation and the release of proinflammatory cytokines that in turn contribute to early synaptic dysfunction in AD. At present, the mechanisms of Aβ3(pE)-42 uptake to astrocytes are unknown and pharmacological interventions that interfere with this process are not available.

Integration of nuclear Ca transients and subnuclear protein shuttling provides a novel mechanism for the regulation of CREB-dependent gene expression.

Nuclear Ca waves elicited by NMDAR and L-type voltage-gated Ca-channels as well as protein transport from synapse-to-nucleus are both instrumental in control of plasticity-related gene expression. At present it is not known whether fast [Ca] transients converge in the nucleus with signaling of synapto-nuclear protein messenger. Jacob is a protein that translocate a signalosome from N-methyl-D-aspartate receptors (NMDAR) to the nucleus and that docks this signalosome to the transcription factor CREB.

Jacob-induced transcriptional inactivation of CREB promotes Aβ-induced synapse loss in Alzheimer's disease.

Synaptic dysfunction caused by soluble β-amyloid peptide (Aβ) is a hallmark of early-stage Alzheimer's disease (AD), and is tightly linked to cognitive decline. By yet unknown mechanisms, Aβ suppresses the transcriptional activity of cAMP-responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that Aβ elicits nucleocytoplasmic trafficking of Jacob, a protein that connects a NMDA-receptor-derived signalosome to CREB, in AD patient brains and mouse hippocampal neurons.

Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer's disease.

Background: The metabolic syndrome is a consequence of modern lifestyle that causes synaptic insulin resistance and cognitive deficits and that in interaction with a high amyloid load is an important risk factor for Alzheimer's disease. It has been proposed that neuroinflammation might be an intervening variable, but the underlying mechanisms are currently unknown.

Methods: We utilized primary neurons to induce synaptic insulin resistance as well as a mouse model of high-risk aging that includes a high amyloid load, neuroinflammation, and diet-induced obesity to test hypotheses on underlying mechanisms.

Multiomics of synaptic junctions reveals altered lipid metabolism and signaling following environmental enrichment.

Membrane lipids and their metabolism have key functions in neurotransmission. Here we provide a quantitative lipid inventory of mouse and rat synaptic junctions. To this end, we developed a multiomics extraction and analysis workflow to probe the interplay of proteins and lipids in synaptic signal transduction from the same sample.

Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function.

Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions.

Neuroplastin expression is essential for hearing and hair cell PMCA expression.

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements.

Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus.

DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3A1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit.

SIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals.

Amphisomes are organelles of the autophagy pathway that result from the fusion of autophagosomes with late endosomes. While biogenesis of autophagosomes and late endosomes occurs continuously at axon terminals, non-degradative roles of autophagy at boutons are barely described. Here, we show that in neurons BDNF/TrkB traffick in amphisomes that signal locally at presynaptic boutons during retrograde transport to the soma.

Caldendrin Directly Couples Postsynaptic Calcium Signals to Actin Remodeling in Dendritic Spines.

Compartmentalization of calcium-dependent plasticity allows for rapid actin remodeling in dendritic spines. However, molecular mechanisms for the spatio-temporal regulation of filamentous actin (F-actin) dynamics by spinous Ca-transients are still poorly defined. We show that the postsynaptic Ca sensor caldendrin orchestrates nano-domain actin dynamics that are essential for actin remodeling in the early phase of long-term potentiation (LTP).

Posttranslational modification impact on the mechanism by which amyloid-β induces synaptic dysfunction.

Oligomeric amyloid-β (Aβ) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ have been identified, among which N-terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms.

Synaptic GluN2B/CaMKII-α Signaling Induces Synapto-Nuclear Transport of ERK and Jacob.

A central pathway in synaptic plasticity couples N-Methyl-D-Aspartate-receptor (NMDAR)-signaling to the activation of extracellular signal-regulated kinases (ERKs) cascade. ERK-dependency has been demonstrated for several forms of synaptic plasticity as well as learning and memory and includes local synaptic processes but also long-distance signaling to the nucleus. It is, however, controversial how NMDAR signals are connected to ERK activation in dendritic spines and nuclear import of ERK.

Isolation of CA1 nuclear enriched fractions from hippocampal slices to study activity-dependent nuclear import of synapto-nuclear messenger proteins.

Studying activity dependent protein expression, subcellular translocation, or phosphorylation is essential to understand the underlying cellular mechanisms of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) induced in acute hippocampal slices are widely accepted as cellular models of learning and memory. There are numerous studies that use live cell imaging or immunohistochemistry approaches to visualize activity dependent protein dynamics.

Cellular distribution of the NMDA-receptor activated synapto-nuclear messenger Jacob in the rat brain.

In previous work, we found that the protein messenger Jacob is involved in N-methyl-D-aspartate receptor (NMDAR) signaling to the nucleus and cAMP response element-binding protein (CREB) mediated gene expression in hippocampal primary neurons. Particularly, extrasynaptic NMDAR activation drives Jacob efficiently into the nucleus where it then induces gene expression that promotes neurodegeneration. However, the protein also translocates to the nucleus in CA1 neurons after Schaffer collateral long-term potentiation (LTP) but not long-term depression (LTD), suggesting that Jacob might be involved in hippocampal and LTP-dependent learning and memory processes.

Hippocampal LTP triggers proteasome-mediated SPAR degradation in CA1 neurons.

Activity-dependent synaptic plasticity is associated with synaptic protein turnover involving the ubiquitin proteasome system (UPS) for protein degradation. In primary hippocampal cell culture, it has been shown that increased or decreased activity of synaptic transmission can regulate the amount of postsynaptic density (PSD) proteins via UPS. However, the specific spatio-temporal dynamic of PSD protein degradation after LTP induction and its downstream signaling pathways remains to be clarify.

Nuclear translocation of jacob in hippocampal neurons after stimuli inducing long-term potentiation but not long-term depression.

Background: In recent years a number of potential synapto-nuclear protein messengers have been characterized that are thought to be involved in plasticity-related gene expression, and that have the capacity of importin- mediated and activity-dependent nuclear import. However, there is a surprising paucity of data showing the nuclear import of such proteins in cellular models of learning and memory. Only recently it was found that the transcription factor cyclic AMP response element binding protein 2 (CREB2) transits to the nucleus during long-term depression (LTD), but not during long-term potentiation (LTP) of synaptic transmission in hippocampal primary neurons.