Modulation of AMPA receptor surface diffusion restores hippocampal plasticity and memory in Huntington’s disease models

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In vitro preparation of prefibrillar intermediates of amyloid-beta and alpha-synuclein

Elucidating the structural properties of early intermediates (protofibrils) on the fibril formation pathway of Abeta and alpha-synuclein, the structural relationship among the different intermediates and their relationship to the structure of the amyloid fibrils is critical for understanding the roles of amyloid fibril formation in the pathogenesis of Alzheimer's and Parkinson's diseases. In this chapter we discuss several methods, developed by different laboratories, that enable the preparation and stabilization of amyloid-beta and alpha-synuclein protofibrillar species of defined morphologies for biochemical, biophysical and toxicity studies

Neurexin-1β Binding to Neuroligin-1 Triggers the Preferential Recruitment of PSD-95 versus Gephyrin through Tyrosine Phosphorylation of Neuroligin-1

Adhesion between neurexin-1β (Nrx1β) and neuroligin-1 (Nlg1) induces early recruitment of the postsynaptic density protein 95 (PSD-95) scaffold; however, the associated signaling mechanisms are unknown. To dissociate the effects of ligand binding and receptor multimerization, we compared conditions in which Nlg1 in neurons was bound to Nrx1β or nonactivating HA antibodies. Time-lapse imaging, fluorescence recovery after photobleaching, and single-particle tracking demonstrated that in addition to aggregating Nlg1, Nrx1β binding stimulates the interaction between Nlg1 and PSD-95. Phosphotyrosine immunoblots and pull-down of gephyrin by Nlg1 peptides in vitro showed that Nlg1 can be phosphorylated at a unique tyrosine (Y782), preventing gephyrin binding. Expression of Nlg1 point mutants in neurons indicated that Y782 phosphorylation controls the preferential binding of Nlg1 to PSD-95 versus gephyrin, and accordingly the formation of inhibitory and excitatory synapses. We propose that ligand-induced changes in the Nlg1 phosphotyrosine level control the balance between excitatory and inhibitory scaffold assembly during synapse formation and stabilization

Gold nanoparticles for selective and remote heating of β-amyloid protein aggregates

5 pages, 3 figures, 2 tables.-- Issue title: "EMRS 2006 Symposium A: Current Trends in Nanoscience - from Materials to Applications" (Nice, France, May 29-Jun 2, 2006)Nanoparticles can be made to respond resonantly to a time-varying electromagnetic field with advantageous results related to the transfer of energy from the exciting field to the nanoparticles. The surface of each particle can be heated up, this heat being transmitted into the immediately surrounding tissue. This enables their use as hyperthermia agents delivering toxic amounts of thermal energy to targeted bodies such as tumours. Heating of nanoparticles in a magnetic field is mainly due to inductive coupling (via eddy currents), and in the case of magnetic particles, loss processes during the reorientation of the magnetization (hysteresis losses) or frictional losses (relaxational losses) if the particle can rotate in an environment of sufficiently low viscosity. We use this method to apply heat locally and remotely, dissolving toxic protein deposits of Aβ1–42 (amyloid deposits) via the combined use of weak microwave fields and gold nanoparticles (AuNP) without any bulk heating. This method can be extended to a number of systems where it may be desirable to remove proteins and other aggregates involved in different pathologiesThis work was supported by Generalitat de Catalunya [CeRBa and Grups Consolidats 2001 SGR 00066 and 2001 SGR 00047)], Ministerio de Educación y Ciencia (MAT2003-01124, BIO 2002-02301 and EET2001-4813) and Direccion de Investigacion de la Universidad de ChilePeer reviewe

Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency

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Nanoparticle-mediated local and remote manipulation of protein aggregation

The local heat delivered by metallic nanoparticles selectively attached to their target can be used as a molecular surgery to safely remove toxic and clogging aggregates. We apply this principle to protein aggregates, in particular to the amyloid beta protein (A beta) involved in Alzheimer's disease (AD), a neurodegenerative disease where unnaturally folded A beta proteins self-assemble and deposit forming amyloid fibrils and plaques. We show the possibility to remotely redissolve these deposits and to interfere with their growth, using the local heat dissipated by gold nanoparticles (AuNP) selectively attached to the aggregates and irradiated with low gigahertz electromagnetic fields. Simultaneous tagging and manipulation by AuNP of A beta at different stages of aggregation allow both, noninvasive exploration and dissolution of molecular aggregates

Lengthening of the stargazin cytoplasmic tail increases synaptic transmission by promoting interaction to deeper domains of PSD-95

PSD-95 is a prominent organizer of the postsynaptic density (PSD) that can present a filamentous orientation perpendicular to the plasma membrane. Interactions between PSD-95 and transmembrane proteins might be particularly sensitive to this orientation, as "long" cytoplasmic tails might be required to reach deeper PSD-95 domains. Extension/retraction of transmembrane protein C-tails offer a new way of regulating binding to PSD-95. Using stargazin as a model, we found that enhancing the apparent length of stargazin C-tail through phosphorylation or by an artificial linker was sufficient to potentiate binding to PSD-95, AMPAR anchoring, and synaptic transmission. A linear extension of stargazin C-tail facilitates binding to PSD-95 by preferentially engaging interaction with the farthest located PDZ domains regarding to the plasma membrane, which present a greater affinity for the stargazin PDZ-domain-binding motif. Our study reveals that the concerted orientation of the stargazin C-tail and PSD-95 is a major determinant of synaptic strength

Functional recruitment of dynamin requires multimeric interactions for efficient endocytosis

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CaMKII Metaplasticity Drives Aβ Oligomer-Mediated Synaptotoxicity

Summary: Alzheimer’s disease (AD) is emerging as a synaptopathology driven by metaplasticity. Indeed, reminiscent of metaplasticity, oligomeric forms of the amyloid-β peptide (oAβ) prevent induction of long-term potentiation (LTP) via the prior activation of GluN2B-containing NMDA receptors (NMDARs). However, the downstream Ca2+-dependent signaling molecules that mediate aberrant metaplasticity are unknown. In this study, we show that oAβ promotes the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) via GluN2B-containing NMDARs. Importantly, we find that CaMKII inhibition rescues both the LTP impairment and the dendritic spine loss mediated by oAβ. Mechanistically resembling metaplasticity, oAβ prevents subsequent rounds of plasticity from inducing CaMKII T286 autophosphorylation, as well as the associated anchoring and accumulation of synaptic AMPA receptors (AMPARs). Finally, prolonged oAβ treatment-induced CaMKII misactivation leads to dendritic spine loss via the destabilization of surface AMPARs. Thus, our study demonstrates that oAβ engages synaptic metaplasticity via aberrant CaMKII activation. : Opazo et al. show that oligomeric and synaptotoxic forms of the Aβ peptide trigger the rapid activation of CaMKII throughout the neuron. They find that aberrant CaMKII activation leads to deficits in long-term potentiation and ultimately synaptic loss via the destabilization of AMPA receptors. Keywords: CaMKII, oligomeric Aβ, NMDAR, GluN2B, AMPAR, Alzheimer’s disease, APP, dendritic spines, metaplasticity, long-term potentiation, LT