N-cadherin: stabilizing synapses

Spines are sites of excitatory synapse formation in central neurons. Alterations in spine structure and function are widely believed to actively contribute to the cellular mechanisms of learning and memory. In this issue, Mendez et al. (2010. J. Cell Biol. doi:10.1083/jcb.201003007) demonstrate a pivotal role for the cell adhesion molecule N-cadherin in activity-mediated spine stabilization, offering a new mechanism for how spine dynamics and stability are regulated by activity in central neurons

Age‐related changes in cerebellar and hypothalamic function accompany non‐microglial immune gene expression, altered synapse organization, and excitatory amino acid neurotransmission deficits

We describe age-related molecular and neuronal changes that disrupt mobility or energy balance based on brain region and genetic background. Compared to young mice, aged C57BL/6 mice exhibit marked locomotor (but not energy balance) impairments. In contrast, aged BALB mice exhibit marked energy balance (but not locomotor) impairments. Age-related changes in cerebellar or hypothalamic gene expression accompany these phenotypes. Aging evokes upregulation of immune pattern recognition receptors and cell adhesion molecules. However, these changes do not localize to microglia, the major CNS immunocyte. Consistent with a neuronal role, there is a marked age-related increase in excitatory synapses over the cerebellum and hypothalamus. Functional imaging of these regions is consistent with age-related synaptic impairments. These studies suggest that aging reactivates a developmental program employed during embryogenesis where immune molecules guide synapse formation and pruning. Renewed activity in this program may disrupt excitatory neurotransmission, causing significant behavioral deficits

Intracellular amyloid beta expression leads to dysregulation of the mitogen-activated protein kinase and bone morphogenetic protein-2 signaling axis.

Alzheimer's disease (AD) is a neurodegenerative syndrome classically depicted by the parenchymal accumulation of extracellular amyloid beta plaques. However, recent findings suggest intraneuronal amyloid beta (iAβ1-42) accumulation precedes extracellular deposition. Furthermore, the pathologic increase in iAβ1-42 has been implicated in dysregulation of cellular mechanisms critically important in axonal transport. Owing to neuronal cell polarity, retrograde and anterograde axonal transport are essential trafficking mechanism necessary to convey membrane bound neurotransmitters, neurotrophins, and endosomes between soma and synaptic interfaces. Although iAβ1-42 disruption of axonal transport has been implicated in dysregulation of neuronal synaptic transmission, the role of iAβ1-42 and its influence on signal transduction involving the mitogen-activated protein kinase (MAPK) and morphogenetic signaling axis are unknown. Our biochemical characterization of intracellular amyloid beta accumulation on MAPK and morphogenetic signaling have revealed increased iAβ1-42 expression leads to significant reduction in ERK 1/2 phosphorylation and increased bone morphogenetic protein 2 dependent Smad 1/5/8 phosphorylation. Furthermore, rescue of iAβ1-42 mediated attenuation of MAPK signaling can be accomplished with the small molecule PLX4032 as a downstream enhancer of the MAPK pathway. Consequently, our observations regarding the dysregulation of these gatekeepers of neuronal viability may have important implications in understanding the iAβ1-42 mediated effects observed in AD

Complement Component C3 Loss leads to Locomotor Deficits and Altered Cerebellar Internal Granule Cell In Vitro Synaptic Protein Expression in C57BL/6 mice

Complement component 3 (C3) expression is increased in the cerebellum of aging mice that demonstrate locomotor impairments and increased excitatory synapse density. However, C3 regulation of locomotion, as well as C3 roles in excitatory synapse function, remain poorly understood. Here, we demonstrate that constitutive loss of C3 function in mice evokes a locomotor phenotype characterized by decreased speed, increased active state locomotor probability, and gait ataxia. C3 loss does not alter metabolism or body mass composition. No evidence of significant muscle weakness or degenerative arthritis was found in C3 knockout mice to explain decreased gait speeds. In an enriched primary cerebellar granule cell culture model, loss of C3 protein results in increased excitatory synaptic density and increased response to KCl depolarization. Our analysis of excitatory synaptic density in the cerebellar internal granule cell and molecular layers did not demonstrate increased synaptic density in vivo, suggesting the presence of compensatory mechanisms regulating synaptic development. Functional deficits in C3 knockout mice are therefore more likely to result from altered synaptic function and/or connectivity than gross synaptic deficits. Our data demonstrate a novel role for complement proteins in cerebellar regulation of locomotor output and control

Kruskal-Wallace test (p < 0.05) with post-hoc pairwise analysis of phospho-Smad 1/5/8 following rh-BMP2 and/or Dorsomorphin treatment of VC or iAβ transduced HPC cells.

<p>Kruskal-Wallace test (p < 0.05) with post-hoc pairwise analysis of phospho-Smad 1/5/8 following rh-BMP2 and/or Dorsomorphin treatment of VC or iAβ transduced HPC cells.</p

iAβ expression leads to relative increase in BMP-2 dependent Smad 1/5/8 phosphorylation.

<p><b>(A)</b> Immunoblot of the phospho-Smad 1/5/8 and total-Smad 1/5/8 in VC or iAβ transduced HEK293 cells following rh-BMP2 stimulation. While total-Smad 1/5/8 levels remain unchanged, an increase in the rh-BMP2 dependent Smad 1/5/8 phosphorylation can be observed in the iAβ transduced cells relative to VC. Two-dimensional gel transformation of phospho-Smad 1/5/8 intensities performed and shown as histogram. Beta-actin used as loading control. <b>(B)</b> Plot of the relative densitometry analysis of phospho-Smad 1/5/8 intensity of biological replicates with data shown as mean ± SE (n = 3) with statistical significance (**p < 0.01). <b>(C)</b> Plot of total-Smad 1/5/8 abundance depicting unaltered levels among all groups. <b>(D)</b> Histogram of phospho-flow cytometry analysis of rh-BMP2 treated VC (gray) or iAβ (black) transduced HEK293 cells. A positive shift in iAβ transduced cells relative to the VC can be seen indicating an increase in the abundance of phospho-Smad 1/5/8. <b>(E)</b> Replicate analysis shown as mean ± SE (n = 3) of the MFI with a statistically significant (**p < 0.01) 4.2-fold increase in MFI. Dixon’s outlier analysis was performed on the replicates and there are no outliers within the dataset that should be excluded (p > 0.05).</p

Kruskal-Wallace test (p < 0.05) with post-hoc pairwise analysis of ERK 1/2 phosphorylation in VC and iAβ transduced HEK293 cells treated in presence or absence of eAβ_1–42.

<p>Kruskal-Wallace test (p < 0.05) with post-hoc pairwise analysis of ERK 1/2 phosphorylation in VC and iAβ transduced HEK293 cells treated in presence or absence of eAβ_1–42.</p