Amyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate.

Amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release is proposed to be a crucial early event leading to synapse dysfunction in Alzheimer's disease (AD). In the present study, we report that the release probability (Pr) at the synapse between the Schaffer collateral (SC) and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production. High nanomolar synthetic oligomeric Aβ also suppresses Pr at the SC-CA1 synapse in wild-type mice.

TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila.

Neuronal amyloid-β (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of Aβ are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type IIIα (PI4KIIIα) reduces neuronal Aβ accumulation and associated neural deficits in a Drosophila model expressing Aβ42.

An Improved Method for Collection of Cerebrospinal Fluid from Anesthetized Mice.

The cerebrospinal fluid (CSF) is a valuable body fluid for analysis in neuroscience research. It is one of the fluids in closest contact with the central nervous system and thus, can be used to analyze the diseased state of the brain or spinal cord without directly accessing these tissues. However, in mice it is difficult to obtain from the cisterna magna due to its closeness to blood vessels, which often contaminate samples.

An Automated Rapid Iterative Negative Geotaxis Assay for Analyzing Adult Climbing Behavior in a Drosophila Model of Neurodegeneration.

Neurodegenerative diseases are frequently associated with a progressive loss of movement ability, reduced life span, and age-dependent neurodegeneration. To understand the mechanism of these cellular events, and their causal relationships with each other, Drosophila melanogaster, with its sophisticated genetic tools and diverse behavioral features, are used as disease models for assessing neurodegenerative phenotypes. Here we describe a high-throughput method to analyze Drosophila adult negative geotaxis behavior, as an indication for possible motor defects associated with neurodegeneration.

An Efficient and Reliable Assay for Investigating the Effects of Hypoxia/Anoxia on Drosophila.

Stroke is a leading cause of death worldwide. Up to one thousand potential drugs or interventions have been developed to treat stroke, out of which ~160 have gone on to clinical trials. However, none of them has been successful.

Downregulation of RBO-PI4KIIIα Facilitates Aβ Secretion and Ameliorates Neural Deficits in Aβ-Expressing .

Phosphoinositides and their metabolizing enzymes are involved in Aβ metabolism and Alzheimer's disease pathogenesis. In yeast and mammals, Eighty-five requiring 3 (EFR3), whose homolog is Rolling Blackout (RBO), forms a plasma membrane-localized protein complex with phosphatidylinositol-4-kinase Type IIIα (PI4KIIIα) and a scaffold protein to tightly control the level of plasmalemmal phosphatidylinositol-4-phosphate (PIP). Here, we report that RBO binds to PI4KIIIα, and that in an Aβ-expressing model, separate genetic reduction of PI4KIIIα and RBO, or pharmacological inhibition of PI4KIIIα ameliorated synaptic transmission deficit, climbing ability decline, premature death, and reduced neuronal accumulation of Aβ Moreover, we found that RBO-PI4KIIIa downregulation increased neuronal Aβ release and that PI4P facilitated the assembly or oligomerization of Aβ in/on liposomes.

Automated rapid iterative negative geotaxis assay and its use in a genetic screen for modifiers of Aβ(42)-induced locomotor decline in Drosophila.

The negative-geotaxis climbing assay is used to efficiently study aging and neurodegeneration in Drosophila. To make it suitable for large-scale study, a method called the rapid iterative negative geotaxis (RING) assay has been established by simultaneously photographing the climbing of multiple groups of flies when they are manually tapped down in test tubes. Here, we automated the assay by using a well-controlled electric motor to drive the tapping, and a homemade program to analyze the climbing height of flies.

The use of MMSE and MoCA in patients with acute ischemic stroke in clinical.

Background: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are brief cognitive screening tools that have been developed for the screening of patients with Mild Cognitive Impairment.

Methods: A total of 105 patients were included in this study, aged 53-89 years, with acute ischemic stroke admitted to hospital and fell into two groups: stroke patients with cognitive impairment (SCI) and controls with no cognitive impairment (n-SCI). The patient's characteristics are collected and regression analyses were performed to predict cognitive impairments.

Intraneuronal accumulation of Aβ42 induces age-dependent slowing of neuronal transmission in Drosophila.

Beta amyloid (Aβ42)-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer's disease (AD). The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aβ42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered.

Age-dependent alterations in the presynaptic active zone in a Drosophila model of Alzheimer's disease.

The accumulation of beta amyloid (Aβ) can cause synaptic impairments, but the characteristics and mechanisms of the synaptic impairment induced by the accumulation of Aβ in Alzheimer's disease (AD) remain unclear. In identified single neurons in a newly developed Drosophila AD model, in which Aβ accumulates intraneuronally, we found an age-dependent reduction in the synaptic vesicle release probability that was associated with a decrease in the density of presynaptic calcium channel clusters and an increase in the presynaptic and postsynaptic contact length. Moreover, these alterations occurred in the absence of presynaptic bouton loss.

Overexpression of human MRP1 in neurons causes resistance to antiepileptic drugs in Drosophila seizure mutants.

Multidrug resistance-associated protein 1 (MRP1), an efflux multidrug transporter, was shown to be elevated in both glia and neurons in seizure focus in refractory epilepsy patients. Up-regulation of MRP1 and other multidrug transporters in perivascular astrocytes was suggested to cause resistance to antiepileptic drugs (AEDs) by reducing the concentration of AEDs at the epileptogenic areas. However, it is not known whether the up-regulation of MRP1 in neurons can cause resistance to AEDs, such as sodium phenytoin (PHT) and valproic acid (VPA).

Rolling blackout is required for synaptic vesicle exocytosis.

Rolling blackout (RBO) is a putative transmembrane lipase required for phospholipase C-dependent phosphatidylinositol 4,5-bisphosphate-diacylglycerol signaling in Drosophila neurons. Conditional temperature-sensitive (TS) rbo mutants display complete, reversible paralysis within minutes, demonstrating that RBO is acutely required for movement. RBO protein is localized predominantly in presynaptic boutons at neuromuscular junction (NMJ) synapses and throughout central synaptic neuropil, and rbo TS mutants display a complete, reversible block of both central and peripheral synaptic transmission within minutes.

Hippocampal theta state in relation to formalin nociception.

In the present study using extracellular electrophysiological recording techniques, we explored the temporal characteristics of hippocampal theta activation in relation to formalin nociception. Results indicate that, compared to hind paw injection of saline, formalin injection in behaving rat evoked biphasic increase in duration of dorsal CA1 theta. Such an increase broadly paralleled animal biphasic behavioral activation, especially lick and moment-to-moment agitated behaviors.

Rolling blackout, a newly identified PIP2-DAG pathway lipase required for Drosophila phototransduction.

The rolling blackout (rbo) gene encodes an integral plasma membrane lipase required for Drosophila phototransduction. Photoreceptors are enriched for the RBO protein, and temperature-sensitive rbo mutants show reversible elimination of phototransduction within minutes, demonstrating an acute requirement for the protein. The block is activity dependent, indicating that the action of RBO is use dependent.