Tau and Amyloid ß Protein in Patient-Derived Aqueous Brain Extracts Act Concomitantly to Disrupt Long-Term Potentiation in Vivo.

Amyloid ß protein (Aß) and tau, the two main proteins implicated in causing Alzheimer's disease (AD), are posited to trigger synaptic dysfunction long before significant synaptic loss occurs in vulnerable circuits. Whereas soluble Aß aggregates from AD brain are well recognized potent synaptotoxins, less is known about the synaptotoxicity of soluble tau from AD or other tauopathy patient brains. Minimally manipulated patient-derived aqueous brain extracts contain the more diffusible native forms of these proteins. Here, we explore how intracerebral injection of Aß and tau present in such aqueous extracts of patient brain contribute to disruption of synaptic plasticity in the CA1 area of the male rat hippocampus. Aqueous extracts of certain AD brains acutely inhibited long-term potentiation (LTP) of synaptic transmission in a manner that required both Aß and tau. Tau-containing aqueous extracts of a brain from a patient with Pick's disease (PiD) also impaired LTP, and diffusible tau from either AD or PiD brain lowered the threshold for AD brain Aß to inhibit LTP. Remarkably, the disruption of LTP persisted for at least 2 weeks after a single injection. These findings support a critical role for diffusible tau in causing rapid onset, persistent synaptic plasticity deficits, and promoting Aß-mediated synaptic dysfunction.SIGNIFICANCE STATEMENT The microtubule-associated protein tau forms relatively insoluble fibrillar deposits in the brains of people with neurodegenerative diseases including Alzheimer's and Pick's diseases. More soluble aggregates of disease-associated tau may diffuse between cells and could cause damage to synapses in vulnerable circuits. We prepared aqueous extracts of diseased cerebral cortex and tested their ability to interfere with synaptic function in the brains of live rats. Tau in these extracts rapidly and persistently disrupted synaptic plasticity and facilitated impairments caused by amyloid ß protein, the other major pathologic protein in Alzheimer's disease. These findings show that certain diffusible forms of tau can mediate synaptic dysfunction and may be a target for therapy.

Gamma-patterned sensory stimulation reverses synaptic plasticity deficits in rat models of early Alzheimer's disease.

Non-invasive sensory stimulation in the range of the brain's gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Here, we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily treatment with 40 Hz sensory stimulation for 2 weeks fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals, which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD.

Hippocampal hyperactivity in a rat model of Alzheimer's disease.

Neuronal network dysfunction is a hallmark of Alzheimer's disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in transgenic McGill-R-Thy1-APP rats (APPtg) at the beginning of extracellular amyloid beta (Aß) deposition. We established two-photon Ca2+ -imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. We did neither observe changes in synaptic inhibition, nor in excitation. Our data support the view that increased intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of Aß-deposition and disease progression.

Cellular Prion Protein Mediates the Disruption of Hippocampal Synaptic Plasticity by Soluble Tau In Vivo.

Intracellular neurofibrillary tangles (NFTs) composed of tau protein are a neuropathological hallmark of several neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). For some time NFTs were considered the primary cause of synaptic dysfunction and neuronal death, however, more recent evidence suggests that soluble aggregates of tau are key drivers of disease. Here we investigated the effect of different tau species on synaptic plasticity in the male rat hippocampus in vivo Intracerebroventricular injection of soluble aggregates formed from either wild-type or P301S human recombinant tau potently inhibited hippocampal long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, tau monomers and fibrils appeared inactive. Neither baseline synaptic transmission, paired-pulse facilitation nor burst response during high-frequency conditioning stimulation was affected by the soluble tau aggregates. Similarly, certain AD brain soluble extracts inhibited LTP in a tau-dependent manner that was abrogated by either immunodepletion with, or coinjection of, a mid-region anti-tau monoclonal antibody (mAb), Tau5. Importantly, this tau-mediated block of LTP was prevented by administration of mAbs selective for the prion protein (PrP). Specifically, mAbs to both the mid-region (6D11) and N-terminus (MI-0131) of PrP prevented inhibition of LTP by both recombinant and brain-derived tau. These findings indicate that PrP is a mediator of tau-induced synaptic dysfunction.SIGNIFICANCE STATEMENT Here we report that certain soluble forms of tau selectively disrupt synaptic plasticity in the live rat hippocampus. Further, we show that monoclonal antibodies to cellular prion protein abrogate the impairment of long-term potentiation caused both by recombinant and Alzheimer's disease brain-derived soluble tau. These findings support a critical role for cellular prion protein in the deleterious synaptic actions of extracellular soluble tau in tauopathies, including Alzheimer's disease. Thus, approaches targeting cellular prion protein, or downstream pathways, might provide an effective strategy for developing therapeutics.

Soluble tau aggregates inhibit synaptic long-term depression and amyloid ß-facilitated LTD in vivo.

Soluble synaptotoxic aggregates of the main pathological proteins of Alzheimer's disease, amyloid ß-protein (Aß) and tau, have rapid and potent inhibitory effects on long-term potentiation (LTP). Although the promotion of synaptic weakening mechanisms, including long-term depression (LTD), is posited to mediate LTP inhibition by Aß, little is known regarding the action of exogenous tau on LTD. The present study examined the ability of different assemblies of full-length human tau to affect LTD in the dorsal hippocampus of the anaesthetized rat. Unlike Aß, intracerebroventricular injection of soluble aggregates of tau (SτAs), but not monomers or fibrils, potently increased the threshold for LTD induction in a manner that required cellular prion protein. However, MTEP, an antagonist of the putative prion protein coreceptor metabotropic glutamate receptor 5, did not prevent the disruption of synaptic plasticity by SτAs. In contrast, systemic treatment with Ro 25-6981, a selective antagonist at GluN2B subunit-containing NMDA receptors, reduced SτA-mediated inhibition of LTD, but not LTP. Intriguingly, SτAs completely blocked Aß-facilitated LTD, whereas a subthreshold dose of SτAs facilitated Aß-mediated inhibition of LTP. Overall, these findings support the importance of cellular prion protein in mediating a range of, sometimes opposing, actions of soluble Aß and tau aggregates with different effector mechanisms on synaptic plasticity.

NLRP3-dependent synaptic plasticity deficit in an Alzheimer's disease amyloidosis model in vivo.

Pro-inflammatory mechanisms have recently emerged as an important component of early Alzheimer's disease (AD) pathogenesis. A particularly attractive therapeutic strategy is to selectively prevent the disruptive effects of activation of the innate immune system in the brain at an early transitional stage by reducing the production or directly neutralizing pro-inflammatory cytokines, in particular IL-1ß and TNF-α. Here we tested their in vivo effects on synaptic plasticity deficits, which provide sensitive and robust measures of synaptic failure, in a rat model of AD amyloidosis. Using electrophysiological techniques we longitudinally studied the effects of the NLRP3 inflammasome inhibitor Mcc950, the IL-1 receptor antagonist (anakinra) and an anti-TNF-α agent (etanercept) in awake freely moving transgenic rats overexpressing AD associated ß-amyloid precursor protein at a pre-plaque stage of amyloidosis. Repeated treatment with Mcc950 reversibly abrogated the inhibition of long-term potentiation. The IL-1 receptor antagonist and etanercept also had a similar beneficial effect on the deficit in synaptic plasticity. Our findings support the clinical development of Mcc950 and clinically available IL-1- and TNF-α-neutralizing agents in early AD.

Amyloid Oligomers and Mature Fibrils Prepared from an Innocuous Protein Cause Diverging Cellular Death Mechanisms.

Despite significant advances, the molecular identity of the cytotoxic species populated during in vivo amyloid formation crucial for the understanding of neurodegenerative disorders is yet to be revealed. In this study lysozyme prefibrillar oligomers and fibrils in both mature and sonicated states have been isolated through an optimized ultrafiltration/ultracentrifugation method and characterized with various optical spectroscopic techniques, atomic force microscopy, and transmission electron microscopy. We examined their level and mode of toxicity on rat pheochromocytoma (PC12) cells in both differentiated and undifferentiated states. We find that oligomers and fibrils display cytotoxic capabilities toward cultured cells in vitro, with oligomers producing elevated levels of cellular injury toward undifferentiated PC12 cells (PC12(undiff)). Furthermore, dual flow cytometry staining experiments demonstrate that the oligomers and mature fibrils induce divergent cellular death pathways (apoptosis and secondary necrosis, respectively) in these PC12 cells. We have also shown that oligomers but not sonicated mature fibrils inhibit hippocampal long term potentiation, a form of synaptic plasticity implicated in learning and memory, in vivo. We conclude that our in vitro and in vivo findings confer a level of resistance toward amyloid fibrils, and that the PC 12-based comparative cytotoxicity assay can provide insights into toxicity differences between differently aggregated protein species.

Peripheral administration of a humanized anti-PrP antibody blocks Alzheimer's disease Aß synaptotoxicity.

Alzheimer's disease (AD) is associated with pathological assembly states of amyloid-ß protein (Aß). Aß-related synaptotoxicity can be blocked by anti-prion protein (PrP) antibodies, potentially allowing therapeutic targeting of this aspect of AD neuropathogenesis. Here, we show that intravascular administration of a high-affinity humanized anti-PrP antibody to rats can prevent the plasticity-disrupting effects induced by exposure to soluble AD brain extract. These results provide an in vivo proof of principle for such a therapeutic strategy.

Secreted amyloid ß-proteins in a cell culture model include N-terminally extended peptides that impair synaptic plasticity.

Evidence for a central role of amyloid ß-protein (Aß) in the genesis of Alzheimer's disease (AD) has led to advanced human trials of Aß-lowering agents. The "amyloid hypothesis" of AD postulates deleterious effects of small, soluble forms of Aß on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble Aß could be therapeutically advantageous, it is important to understand the full range of soluble Aß derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, ∼8 kDa Aß species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded Aß40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of Aß-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of Aß. These N-terminally extended Aß-containing monomeric fragments are distinct from soluble Aß oligomers formed from Aß1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing ß-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic Aß-containing species can arise from APP processing events N-terminal to the classical ß-secretase cleavage site.

Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins.

How the two pathognomonic proteins of Alzheimer's disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic and recombinant forms of these proteins are known to act concurrently to acutely inhibit long-term potentiation (LTP). Here, we examined the effect of early amyloidosis on the acute disruptive action of synaptotoxic tau prepared from recombinant protein and tau in patient-derived aqueous brain extracts. We also explored the persistence of the inhibition of LTP by different synaptotoxic tau preparations. A single intracerebral injection of aggregates of recombinant human tau that had been prepared by either sonication of fibrils (SτAs) or disulfide bond formation (oTau) rapidly and persistently inhibited LTP in rat hippocampus. The threshold for the acute inhibitory effect of oTau was lowered in amyloid precursor protein (APP)-transgenic rats. A single injection of synaptotoxic tau-containing AD or Pick's disease brain extracts also inhibited LTP, for over two weeks. Remarkably, the persistent disruption of synaptic plasticity by patient-derived brain tau was rapidly reversed by a single intracerebral injection of different anti-tau monoclonal antibodies, including one directed to a specific human tau amino acid sequence. We conclude that patient-derived LTP-disrupting tau species persist in the brain for weeks, maintaining their neuroactivity often in concert with Aß. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Do tau-synaptic long-term depression interactions in the hippocampus play a pivotal role in the progression of Alzheimer's disease?

Cognitive decline in Alzheimer's disease correlates with the extent of tau pathology, in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus. Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-ß or long-term depression, a form of synaptic weakening involved in learning and memory, share similar mechanisms. Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging. Conversely, certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau, in particular, phosphorylation at residue Ser396. Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau (hyper)phosphorylation. We first summarize experimental evidence regarding tau-long-term depression interactions, followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer's disease. Finally, we conclude with some thoughts and perspectives on future research about these interactions.

Alzheimer's disease brain-derived amyloid-ß-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein.

Synthetic amyloid-ß protein (Aß) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aß in vitro is controversial. Here we report that intracerebroventricular injection of Aß-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aß. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aß-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aß. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aß, did not significantly affect the Aß-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aß dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aß.

Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo.

One of the most clinically advanced forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear. We hypothesized that antibodies to Abeta could exert a beneficial action by directly neutralizing potentially synaptotoxic soluble Abeta species in the brain. Intracerebroventricular injection of naturally secreted human Abeta inhibited long-term potentiation (LTP), a correlate of learning and memory, in rat hippocampus in vivo but a monoclonal antibody to Abeta completely prevented the inhibition of LTP when injected after Abeta. Size fractionation showed that Abeta oligomers, not monomers or fibrils, were responsible for inhibiting LTP, and an Abeta antibody again prevented such inhibition. Active immunization against Abeta was partially effective, and the effects correlated positively with levels of antibodies to Abeta oligomers. The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Abeta oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.

GluN2B subunit-containing NMDA receptor antagonists prevent Abeta-mediated synaptic plasticity disruption in vivo.

Currently, treatment with the relatively low-affinity NMDA receptor antagonist memantine provides limited benefit in Alzheimer's disease (AD). One probable dose-limiting factor in the use of memantine is the inhibition of NMDA receptor-dependent synaptic plasticity mechanisms believed to underlie certain forms of memory. Moreover, amyloid-beta protein (Abeta) oligomers that are implicated in causing the cognitive deficits of AD potently inhibit this form of plasticity. Here we examined if subtype-preferring NMDA receptor antagonists could preferentially protect against the inhibition of NMDA receptor-dependent plasticity of excitatory synaptic transmission by Abeta in the hippocampus in vivo. Using doses that did not affect control plasticity, antagonists selective for NMDA receptors containing GluN2B but not other GluN2 subunits prevented Abeta(1-42) -mediated inhibition of plasticity. Evidence that the proinflammatory cytokine TNFalpha mediates this deleterious action of Ass was provided by the ability of TNFalpha antagonists to prevent Abeta(1-42) inhibition of plasticity and the abrogation of a similar disruptive effect of TNFalpha using a GluN2B-selective antagonist. Moreover, at nearby synapses that were resistant to the inhibitory effect of TNFalpha, Abeta(1-42) did not significantly affect plasticity. These findings suggest that preferentially targeting GluN2B subunit-containing NMDARs may provide an effective means of preventing cognitive deficits in early Alzheimer's disease.

Long-Term Depression-Inducing Low Frequency Stimulation Enhances p-Tau181 and p-Tau217 in an Age-Dependent Manner in Live Rats.

BACKGROUND: Cognitive decline in Alzheimer's disease (AD) correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of cerebrospinal fluid or blood levels of phosphorylated tau (p-Tau) at residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) are proposed to be particularly sensitive markers of preclinical AD, the generation of p-Tau during brain activity is poorly understood. OBJECTIVE: To study whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can be enhanced by physiological synaptic long-term depression (LTD) which has been linked to the enhancement of p-Tau in hippocampus. METHODS: In vivo electrophysiology was performed in urethane anesthetized young adult and aged male rats. Low frequency electrical stimulation (LFS) was used to induce LTD at CA3 to CA1 synapses. The expression level of p-Tau and total tau was measured in dorsal hippocampus using immunofluorescent staining and/or western blotting. RESULTS: We found that LFS enhanced p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 appeared less sensitive to LFS. Pharmacological antagonism of either N-methyl-D-aspartate or metabotropic glutamate 5 receptors inhibited the elevation of both p-Tau181 and p-Tau217. Targeting the integrated stress response, which increases with aging, using a small molecule inhibitor ISRIB, prevented the enhancement of p-Tau by LFS in aged rats. CONCLUSION: Together, our data provide a novel in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation at key sites in health and aging.

Inherent anti-amyloidogenic activity of human immunoglobulin gamma heavy chains.

We have previously shown that a subpopulation of naturally occurring human IgGs were cross-reactive against conformational epitopes on pathologic aggregates of Abeta, a peptide that forms amyloid fibrils in the brains of patients with Alzheimer disease, inhibited amyloid fibril growth, and dissociated amyloid in vivo. Here, we describe similar anti-amyloidogenic activity that is a general property of free human Ig gamma heavy chains. A gamma(1) heavy chain, F1, had nanomolar binding to an amyloid fibril-related conformational epitope on synthetic oligomers and fibrils as well as on amyloid-laden tissue sections. F1 did not bind to native Abeta monomers, further indicating the conformational nature of its binding site. The inherent anti-amyloidogenic activity of Ig gamma heavy chains was demonstrated by nanomolar amyloid fibril and oligomer binding by polyclonal and monoclonal human heavy chains that were isolated from inert or weakly reactive antibodies. Most importantly, the F1 heavy chain prevented in vitro fibril growth and reduced in vivo soluble Abeta oligomer-induced impairment of rodent hippocampal long term potentiation, a cellular mechanism of learning and memory. These findings demonstrate that free human Ig gamma heavy chains comprise a novel class of molecules for developing potential therapeutics for Alzheimer disease and other amyloid disorders. Moreover, establishing the molecular basis for heavy chain-amyloidogenic conformer interactions should advance understanding on the types of interactions that these pathologic assemblies have with biological molecules.

A monoclonal antibody against synthetic Aß dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aß.

Diverse lines of evidence indicate that pre-fibrillar, diffusible assemblies of the amyloid ß-protein (Aß) play an important role in Alzheimer's disease pathogenesis. Although the precise molecular identity of these soluble toxins remains unsettled, recent experiments suggest that sodium dodecyl sulfate (SDS)-stable Aß dimers may be the basic building blocks of Alzheimer's disease-associated synaptotoxic assemblies and as such present an attractive target for therapeutic intervention. In the absence of sufficient amounts of highly pure cerebral Aß dimers, we have used synthetic disulfide cross-linked dimers (free of Aß monomer or fibrils) to generate conformation-specific monoclonal antibodies. These dimers aggregate to form kinetically trapped protofibrils, but do not readily form fibrils. We identified two antibodies, 3C6 and 4B5, which preferentially bind assemblies formed from covalent Aß dimers, but do not bind to Aß monomer, amyloid precursor protein, or aggregates formed by other amyloidogenic proteins. Monoclonal antibody 3C6, but not an IgM isotype-matched control antibody, ameliorated the plasticity-disrupting effects of Aß extracted from the aqueous phase of Alzheimer's disease brain, thus suggesting that 3C6 targets pathogenically relevant Aß assemblies. These data prove the usefulness of covalent dimers and their assemblies as immunogens and recommend further investigation of the therapeutic and diagnostic utility of monoclonal antibodies raised to such assemblies.

Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer's disease amyloidosis.

Synaptic dysfunction is a likely proximate cause of subtle cognitive impairment in early Alzheimer's disease. Soluble oligomers are the most synaptotoxic forms of amyloid ß-protein (Aß) and mediate synaptic plasticity disruption in Alzheimer's disease amyloidosis. Because the presence and extent of cortisol excess in prodromal Alzheimer's disease predicts the onset of cognitive symptoms we hypothesised that corticosteroids would exacerbate the inhibition of hippocampal synaptic long-term potentiation in a rat model of Alzheimer's disease amyloidosis. In a longitudinal experimental design using freely behaving pre-plaque McGill-R-Thy1-APP male rats, three injections of corticosterone or the glucocorticoid methylprednisolone profoundly disrupted long-term potentiation induced by strong conditioning stimulation for at least 2 months. The same treatments had a transient or no detectible detrimental effect on synaptic plasticity in wild-type littermates. Moreover, corticosterone-mediated cognitive dysfunction, as assessed in a novel object recognition test, was more persistent in the transgenic animals. Evidence for the involvement of pro-inflammatory mechanisms was provided by the ability of the selective the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome inhibitor Mcc950 to reverse the synaptic plasticity deficit in corticosterone-treated transgenic animals. The marked prolongation of the synaptic plasticity disrupting effects of brief corticosteroid excess substantiates a causal role for hypothalamic-pituitary-adrenal axis dysregulation in early Alzheimer's disease.

Persistent inhibition of hippocampal long-term potentiation in vivo by learned helplessness stress.

The persistent cognitive disruptive effects of stress have been strongly implicated in the pathophysiology of depression and post-traumatic stress disorder. Here we examined factors influencing the time course of recovery from the inhibitory effect of acute inescapable stressors on the ability to induce long-term potentiation (LTP) in the dorsal hippocampus in vivo. We tested different forms of LTP, different stressors and different inbred strains of rats. Acute elevated platform stress completely, but transiently (<3 h), inhibited induction of both NMDA receptor-dependent LTP induced by a standard high frequency (200 Hz) conditioning stimulus and an additional LTP that required voltage-dependent Ca(2+) channel activation triggered by strong (400 Hz) conditioning stimulation. In contrast, acute inescapable footshock stress, used to study learned helplessness, inhibited LTP for at least 4 weeks. Contrary to expectations, there was no clear relationship between the ability of the footshock to trigger helpless behavior, a model of stress-induced depression, and the magnitude of LTP inhibition. Moreover, LTP did not appear to be affected by genetic susceptibility to learned helplessness, a model of genetic vulnerability to depression. This long-lasting synaptic plasticity disruption may underlie persistent impairment of hippocampus-dependent cognition by excessive acute inescapable stress.

Silk fibroin safety in the eye: a review that highlights a concern.

The biomedical use of silk as a suture dates back to antiquity. Fibroin is the structural element that determines the strength of silk and here we consider the safety of fibroin in its role in ophthalmology. The high mechanical strength of silk meant sufficiently thin threads could be made for eye microsurgery, but such usage was all but superseded by synthetic polymer sutures, primarily because silk in its entirety was more inflammatory. Significant immunological response can normally be avoided by careful manufacturing to provide high purity fibroin, and it has been utilised in this form for tissue engineering an array of fibre and film substrata deployed in research with cells of the eye. Films of fibroin can also be made transparent, which is a required property in the visual pathway. Transparent layers of corneal epithelial, stromal and endothelial cells have all been demonstrated with maintenance of phenotype, as have constructs supporting retinal cells. Fibroin has a lack of demonstrable infectious agent transfer, an ability to be sterilised and prepared with minimal contamination, long-term predictable degradation and low direct cytotoxicity. However, there remains a known ability to be involved in amyloid formation and potential amyloidosis which, without further examination, is enough to currently question whether fibroin should be employed in the eye given its innervation into the brain.