A novel 14mer peptide, T14, is associated with age-dependent behaviour in female mice.

Age-related cognitive decline presents a healthcare challenge. While age-related mechanisms are mainly studied in humans, animal models provide key insights. Despite evidence of sex-specific differences in aging and cognition, the impact of age on female rodent behaviour is underexplored.

A Novel 14mer Peptide Inhibits Autophagic Flux via Selective Activation of the mTORC1 Signalling Pathway: Implications for Alzheimer's Disease.

During development, a 14mer peptide, T14, modulates cell growth via the α-7 nicotinic acetylcholine receptor (α7 nAChR). However, this process could become excitotoxic in the context of the adult brain, leading to pathologies such as Alzheimer's disease (AD). Recent work shows that T14 acts selectively via the mammalian target of rapamycin complex 1 (mTORC1).

Oxidative Stress Triggers a Pivotal Peptide Linked to Alzheimer's Disease.

An aberrant recapitulation of a developmental mechanism driven by a 14 mer peptide ('T14') derived from acetylcholinesterase (AChE) has been implicated in Alzheimer's disease. T14 was suggested as an upstream driver of neurodegeneration due to its ability to stimulate the production of phosphorylated tau and amyloid beta. The activation of this mechanism in adulthood is thought to be brought upon by insult to the primarily vulnerable subcortical nuclei.

Rodent Models of Alzheimer's Disease: Past Misconceptions and Future Prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective treatments, not least due to the lack of authentic animal models. Typically, rodent models recapitulate the effects but not causes of AD, such as cholinergic neuron loss: lesioning of cholinergic neurons mimics the cognitive decline reminiscent of AD but not its neuropathology. Alternative models rely on the overexpression of genes associated with familial AD, such as amyloid precursor protein, or have genetically amplified expression of mutant tau.

Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid.

This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little-known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre-symptomatic stages of the disease.

A Novel Peptide Driving Neurodegeneration Appears Exclusively Linked to the α7 Nicotinic Acetylcholine Receptor.

T14, a 14mer peptide, is significantly increased in the pre-symptomatic Alzheimer's disease brain, and growing evidence implies its pivotal role in neurodegeneration. Here, we explore the subsequent intracellular events following binding of T14 to its target α7 nicotinic acetylcholine receptor (nAChR). Specifically, we test how various experimental manipulations of PC12 cells impact T14-induced functional outcomes.

Antagonism of a key peptide 'T14' driving neurodegeneration: Evaluation of a next generation therapeutic.

T14, a 14mer peptide derived from the C-terminus of acetylcholinesterase (AChE) is a signalling molecule that could drive neurodegeneration via the alpha 7 nicotinic acetylcholine receptor. Its levels increase as Alzheimer's pathology progresses; however, a cyclic variant of the compound, NBP14, can block the effects of the endogenous linear counterpart in-vitro, ex vivo, and in vivo. Here, we explore the antagonistic potential of two 6mer peptides, NBP6A and NBP6B.

A novel peptide 'T14' reflects age and photo-aging in human skin.

T14 is a 14mer peptide derived from the C-terminus of acetylcholinesterase (AChE). Once cleaved, it is independently bioactive of the parent molecule and enhances calcium influx in different cell types, in a range of scenarios: it binds to an allosteric site selectively on the alpha-7 receptor, where it modulates calcium influx and is thus a potential trophic agent, as already reported in a range of normal developmental scenarios. However, if inappropriately activated, this erstwhile beneficial effect converts to a toxic one, resulting in pathologies as disparate as Alzheimer's and various metastatic cancers.

A Novel Bioactive Peptide, T14, Selectively Activates mTORC1 Signalling: Therapeutic Implications for Neurodegeneration and Other Rapamycin-Sensitive Applications.

T14 modulates calcium influx via the α-7 nicotinic acetylcholine receptor to regulate cell growth. Inappropriate triggering of this process has been implicated in Alzheimer's disease (AD) and cancer, whereas T14 blockade has proven therapeutic potential in in vitro, ex vivo and in vivo models of these pathologies. Mammalian target of rapamycin complex 1 (mTORC1) is critical for growth, however its hyperactivation is implicated in AD and cancer.

Antagonising a novel toxin "T14" in Alzheimer's disease: Comparison of receptor blocker versus antibody effects in vitro.

A 14mer peptide, T14, is a possible signaling molecule driving neurodegeneration. Its levels are doubled in the Alzheimer brain, but its effects can be blocked at the target alpha-7 receptor by a cyclised variant, 'NBP14', which has beneficial effects, in a transgenic mouse model, on the behavioral and histochemical profile. Since the antagonism of T14 has evident therapeutic potential, we explore here an alternative method of preventing its action by comparing the efficacy of NBP14 with a proprietorial polyclonal antibody against T14, 'Ab-19', at inhibiting three distinct effects of the peptide in PC12 cells: calcium influx, cell viability and compensatory acetylcholinesterase (AChE) release.

Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease.

The substantia nigra is generally considered to show significant cell loss not only in Parkinson's but also in Alzheimer's disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo.

When a trophic process turns toxic: Alzheimer's disease as an aberrant recapitulation of a developmental mechanism.

Here we review the idea that Alzheimer's disease (AD) results from aberrant activation of a normal developmental mechanism. This process operates in primarily vulnerable, subcortical nuclei with a distinguishing embryological provenance: the basal rather than the alar plate. All cells are dependent for growth on calcium influx yet these neurons retain a sensitivity to trophic factors into maturity.

A novel process driving Alzheimer's disease validated in a mouse model: Therapeutic potential.

Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood.

Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology.

Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques.

Protective and reversal actions of a novel peptidomimetic against a pivotal toxin implicated in Alzheimer's disease.

Despite the many attempts to understand the aetiology of Alzheimer's disease, the basic mechanisms accounting for the progressive cycle of neuronal loss are still unknown. Previous work has suggested that the pivotal molecule mediating neurodegeneration could be an independently acting peptide cleaved from acetylcholinesterase. This previously unidentified agent acts as a signalling molecule in selectively vulnerable groups of cells where erstwhile developmental mechanisms are activated inappropriately to have a toxic effect in the context of the mature brain.

A Multidisciplinary Approach Reveals an Age-Dependent Expression of a Novel Bioactive Peptide, Already Involved in Neurodegeneration, in the Postnatal Rat Forebrain.

The basal forebrain has received much attention due to its involvement in multiple cognitive functions, but little is known about the basic neuronal mechanisms underlying its development, nor those mediating its primary role in Alzheimer’s disease. We have previously suggested that a novel 14-mer peptide, ‘T14’, could play a pivotal role in Alzheimer’s disease, via reactivation of a developmental signaling pathway. In this study, we have characterized T14 in the context of post-natal rat brain development, using a combination of different techniques.

Modulatory Effects of a Novel Cyclized Peptide in Reducing the Expression of Markers Linked to Alzheimer's Disease.

Despite many studies attempt to identify the primary mechanisms underlying neurodegeneration in Alzheimer's disease (AD), the key events still remain elusive. We have previously shown that a peptide cleaved from the acetylcholinesterase (AChE) C-terminus (T14) can play a pivotal role as a signaling molecule in neurodegeneration, via its interaction with the α7 nicotinic acetylcholine receptor. The main goal of this study is to determine whether a cyclized variant (NBP14) of the toxic AChE-derived peptide can antagonize the effects of its linear counterpart, T14, in modulating well-known markers linked to neurodegeneration.

An Alternative Approach to Study Primary Events in Neurodegeneration Using Ex Vivo Rat Brain Slices.

Despite numerous studies that attempt to develop reliable animal models which reflecting the primary processes underlying neurodegeneration, very few have been widely accepted. Here, we propose a new procedure adapted from the well-known ex vivo brain slice technique, which offers a closer in vivo-like scenario than in vitro preparations, for investigating the early events triggering cell degeneration, as observed in Alzheimer's disease (AD). This variation consists of simple and easily reproducible steps, which enable preservation of the anatomical cytoarchitecture of the selected brain region and its local functionality in a physiological milieu.

A Novel Model to Investigate the Underlying Mechanisms in Alzheimer's Disease.

Currently there is no widely accepted animal model reproducing the full pathological profile of Alzheimer's disease (AD), since the basic mechanisms of neurodegeneration are still poorly understood. We have proposed that the interaction between the α7 nicotinic acetylcholine receptor (α7-nAChR) and a recently discovered toxic peptide, cleaved from the acetylcholinesterase (AChE) C-terminus, could account for the aberrant processes occurring in AD. In this article we describe a new application on model procedure, which combines the advantages of both and preparations, to study the effects of the AChE-derived peptide on the rat basal forebrain (BF).

Optical imaging of the rat brain suggests a previously missing link between top-down and bottom-up nervous system function.

Optical imaging with voltage-sensitive dyes enables the visualization of extensive yet highly transient coalitions of neurons (assemblies) operating throughout the brain on a subsecond time scale. We suggest that operating at the mesoscale level of brain organization, neuronal assemblies may provide a functional link between "bottom-up" cellular mechanisms and "top-down" cognitive ones within anatomically defined regions. We demonstrate in rat brain slices how varying spatiotemporal dynamics of assemblies reveal differences not previously appreciated between: different stages of development in cortical versus subcortical brain areas, different sensory modalities (hearing versus vision), different classes of psychoactive drugs (anesthetics versus analgesics), different effects of anesthesia linked to hyperbaric conditions and, , depths of anesthesia.

The Features and Functions of Neuronal Assemblies: Possible Dependency on Mechanisms beyond Synaptic Transmission.

"Neuronal assemblies" are defined here as coalitions within the brain of millions of neurons extending in space up to 1-2 mm, and lasting for hundreds of milliseconds: as such they could potentially link bottom-up, micro-scale with top-down, macro-scale events. The perspective first compares the features versus of this underappreciated "meso-scale" level of brain processing, secondly considers the various diverse functions in which assemblies may play a pivotal part, and thirdly analyses whether the surprisingly spatially extensive and prolonged temporal properties of assemblies can be described exclusively in terms of classic synaptic transmission or whether additional, different types of signaling systems are likely to operate. Based on our own voltage-sensitive dye imaging (VSDI) data acquired we show how restriction to only one signaling process, i.

Tumor cell migration is inhibited by a novel therapeutic strategy antagonizing the alpha-7 receptor.

A 14mer peptide (T14) derived from the C-terminus of acetylcholinesterase (AChE) selectively activates metastatic breast cancer cells via the alpha-7 nicotinic receptor (α7 nAChR). This naturally occurring peptide is also present in brain, is elevated in Alzheimer's disease, and is antagonised by a cyclized variant (NBP-14). Here we investigated the effects of NBP-14 in six different cancer cell lines, primary leukemia B-cells and normal B-cells.

Don't forget the dose: Improving computed tomography dosing for pediatric appendicitis.

Background: A pediatric computed tomography (CT) radiation dose reduction program was implemented throughout our children's associated hospital system in 2010. We hypothesized that the CT dose received for evaluation of appendicitis in children would be significantly higher among the 40 referral, nonmember hospitals (NMH) than the 9 member hospitals (MH).

Methods: Preoperative CTs of pediatric (<18years) appendectomy patients between April 2012 and April 2015 were reviewed.

Prevalence of Pancreatic Steatosis at a Pediatric Tertiary Care Center.

Objectives: Pancreatic steatosis in adults has been proposed to be associated with obesity; however, data on pancreatic steatosis in children are lacking. Our study aimed to measure the prevalence of pancreatic steatosis in children and to examine its association with obesity and nonalcoholic fatty liver disease.

Methods: This is a retrospective chart review study of 232 patients 2 to 18 years old who underwent abdominal computed tomographic imaging in the emergency department or inpatient ward within a 1-year time span and from whom demographics, anthropometrics, and medical history were obtained.

(I) Pharmacological profiling of a novel modulator of the α7 nicotinic receptor: Blockade of a toxic acetylcholinesterase-derived peptide increased in Alzheimer brains.

The primary cause of Alzheimer's disease is unlikely to be the much studied markers amyloid beta or tau. Their widespread distribution throughout the brain does not account for the specific identity and deep subcortical location of the primarily vulnerable neurons. Moreover an unusual and intriguing feature of these neurons is that, despite their diverse transmitters, they all contain acetylcholinesterase.