Synaptic AMPA Receptor Plasticity and Behavior

The ability to change behavior likely depends on the selective strengthening and weakening of brain synapses. The cellular models of synaptic plasticity, long-term potentiation (LTP) and depression (LTD) of synaptic strength, can be expressed by the synaptic insertion or removal of AMPA receptors (AMPARs), respectively. We here present an overview of studies that have used animal models to show that such AMPAR trafficking underlies several experience-driven phenomena—from neuronal circuit formation to the modification of behavior. We argue that monitoring and manipulating synaptic AMPAR trafficking represents an attractive means to study cognitive function and dysfunction in animal models

Engineering of specific bacteriophages for early diagnosis of Alzheimer′s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting a large proportion of the human population worldwide with great impact on social and economic level. At molecular level, AD is characterized by an increased deposition of plaques, which consist of amyloid-beta however, it is not the amyloid-beta in plaques, but amyloid-beta in soluble oligomeric form that impairs synaptic function and memory encoding. The limitations imposed by the blood-brain barrier (BBB) have hindered the development of new diagnostic/therapeutic techniques. Also, AD-treatments that target plaques have proven to be ineffective, therefore it is important to find diagnostic and therapeutic tools that selectively target amyloid-beta in oligomeric form. Peptie ligands that selectively recognize AB-oligomers are available, however they are not able to cross the BBB. To overcome this limitation, the development and application of viruses has become a very interesting tool. Bacteriophages (or phages – virus that only infect bacterial cells) can bypass the BBB and can be genetically and chemically manipulated in order to recognize and target specific biomarkers commonly used for AD diagnostic. The present work describes the development of a bacteriophage-based system that can be capable of diagnose AD at an early stage by shuttling amyloid-beta specific ligands across the BBB. Phages were genetically engineered with two peptide sequences described to selectively recognize amyloid-beta oligomers in order to target and visualize amyloid-beta aggregates in the brain. Future work will be devoted to test this system in AD-mouse models for diagnosis purposes at an early stage of the disease. If successful, this approach will provide the neuroscience community with a promising tool for AD early diagnose

A bacteriophage-based platform for early diagnosis of Alzheimers disease

Book of Abstracts of CEB Annual Meeting 2017[Excerpt] Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting a large proportion of the human population worldwide. One hallmark of AD is the increased deposition of plaques, which consist of amyloid-beta (AB) peptide, a key molecule to cause AD onset and progression. However, it is not AB immobilized in plaques, but in the still-soluble oligomeric/fibrillar form that impairs synaptic function and memory encoding. It is therefore important to develop tools that selectively target AB in oligomeric/fibrillar form, to diagnose and neutralize these detrimental AB-clusters during the early stages of the disease. Homing peptides that selectively recognize AB-oligomers and fibrils have been described: AB30-39, reactive for AB fibrils and AB33-42, reactive to fibrils and oligomers [1]. However, these peptides are unable to cross the blood-brain barrier (BBB) by themselves. To overcome this limitation, viruses became a very interesting tool given their versatility to be modified through genetic or chemical manipulation. Bacteriophages (phages), are viruses that only infect bacteria (a major advantage in terms of safety when therapeutic use in humans is envisaged). M13KE is one of the most widely used phage which has been reported as capable to cross the BBB [2]. [...]info:eu-repo/semantics/publishedVersio

The Expression of Epac2 and GluA3 in an Alzheimer's Disease Experimental Model and Postmortem Patient Samples

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by amyloid beta (Aβ) and hyperphosphorylated tau accumulation in the brain. Recent studies indicated that memory retrieval, rather than memory formation, was impaired in the early stage of AD. Our previous study reported that pharmacological activation of hippocampal Epac2 promoted memory retrieval in C57BL/6J mice. A recent study suggested that pharmacological inhibition of Epac2 prevented synaptic potentiation mediated by GluA3-containing AMPARs. In this study, we aimed to investigate proteins associated with Epac2-mediated memory in hippocampal postmortem samples of AD patients and healthy controls compared with the experimental AD model J20 and wild-type mice. Epac2 and phospho-Akt were downregulated in AD patients and J20 mice, while Epac1 and phospho-ERK1/2 were not altered. GluA3 was reduced in J20 mice and tended to decrease in AD patients. PSD95 tended to decrease in AD patients and J20. Interestingly, AKAP5 was increased in AD patients but not in J20 mice, implicating its role in tau phosphorylation. Our study points to the downregulation of hippocampal expression of proteins associated with Epac2 in AD. </p

M13 phage grafted with peptide motifs as a tool to detect amyloid- oligomers in brain tissue

Oligomeric clusters of amyloid- (A) are one of the major biomarkers for Alzheimers disease (AD). However, proficient methods to detect A-oligomers in brain tissue are lacking. Here we show that synthetic M13 bacteriophages displaying A-derived peptides on their surface preferentially interact with A-oligomers. When exposed to brain tissue isolated from APP/PS1-transgenic mice, these bacteriophages detect small-sized A-aggregates in hippocampus at an early age, prior to the occurrence of A-plaques. Similarly, the bacteriophages reveal the presence of such small A-aggregates in post-mortem hippocampus tissue of ADpatients. These results advocate bacteriophages displaying A-peptides as a convenient and low-cost tool to identify A-oligomers in post-mortem brain tissue of AD-model mice and AD patients.FCT -Fundação para a Ciência e a Tecnologia(SFRH/BD/101171/2014)info:eu-repo/semantics/publishedVersio

Measuring Behavior in the Home Cage : Study Design, Applications, Challenges, and Perspectives

FUNDING This research was supported by NIH grants R00AG056662, P20GM125528, AG057424 to WS and SLPeer reviewedPublisher PD

The Journal of Physiology Neuroscience The developmental stages of synaptic plasticity

Abstract The brain is programmed to drive behaviour by precisely wiring the appropriate neuronal circuits. Wiring and rewiring of neuronal circuits largely depends on the orchestrated changes in the strengths of synaptic contacts. Here, we review how the rules of synaptic plasticity change during development of the brain, from birth to independence. We focus on the changes that occur at the postsynaptic side of excitatory glutamatergic synapses in the rodent hippocampus and neocortex. First we summarize the current data on the structure of synapses and the developmental expression patterns of the key molecular players of synaptic plasticity, N -methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as pivotal kinases (Ca 2+ /calmodulin-dependent protein kinase II, protein kinase A, protein kinase C) and phosphatases (PP1, PP2A, PP2B). In the second part we relate these findings to important characteristics of the emerging network. We argue that the concerted and gradual shifts in the usage of plasticity molecules comply with the changing need for (re)wiring neuronal circuits

The developmental stages of synaptic plasticity

The brain is programmed to drive behaviour by precisely wiring the appropriate neuronal circuits. Wiring and rewiring of neuronal circuits largely depends on the orchestrated changes in the strengths of synaptic contacts. Here, we review how the rules of synaptic plasticity change during development of the brain, from birth to independence. We focus on the changes that occur at the postsynaptic side of excitatory glutamatergic synapses in the rodent hippocampus and neocortex. First we summarize the current data on the structure of synapses and the developmental expression patterns of the key molecular players of synaptic plasticity, N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as pivotal kinases (Ca(2+)/calmodulin-dependent protein kinase II, protein kinase A, protein kinase C) and phosphatases (PP1, PP2A, PP2B). In the second part we relate these findings to important characteristics of the emerging network. We argue that the concerted and gradual shifts in the usage of plasticity molecules comply with the changing need for (re)wiring neuronal circuit

Metabotropic NMDA receptor function is required for β-amyloid-induced synaptic depression

The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer's disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer's diseas

The prion protein as a receptor for amyloid-beta

Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Laurén et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c