PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis.

We show that amyloid-β (Aβ) triggers a conformational change in the scaffolding protein filamin A (FLNA) to induce FLNA associations with α7-nicotinic acetylcholine receptor (α7nAChR) and toll-like receptor 4 (TLR4). These aberrant associations respectively enable Aβ's toxic signaling via α7nAChR to hyperphosphorylate tau protein, and TLR4 activation to release inflammatory cytokines. PTI-125 is a small molecule that preferentially binds altered FLNA and restores its native conformation, restoring receptor and synaptic activities and reducing its α7nAChR/TLR4 associations and downstream pathologies.

Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling.

Prenatal cocaine exposure causes profound changes in neurobehavior as well as synaptic function and structure with compromised glutamatergic transmission. Since synaptic health and glutamatergic activity are tightly regulated by brain-derived neurotrophic factor (BDNF) signaling through its cognate tyrosine receptor kinase B (TrkB), we hypothesized that prenatal cocaine exposure alters BDNF-TrkB signaling during brain development. Here we show prenatal cocaine exposure enhances BDNF-TrkB signaling in hippocampus and prefrontal cortex (PFCX) of 21-day-old rats without affecting the expression levels of TrkB, P75NTR, signaling molecules, NMDA receptor-NR1 subunit as well as proBDNF and BDNF.

Prenatal cocaine exposure uncouples mGluR1 from Homer1 and Gq Proteins.

Cocaine exposure during gestation causes protracted neurobehavioral changes consistent with a compromised glutamatergic system. Although cocaine profoundly disrupts glutamatergic neurotransmission and in utero cocaine exposure negatively affects metabotropic glutamate receptor-type 1 (mGluR1) activity, the effect of prenatal cocaine exposure on mGluR1 signaling and the underlying mechanism responsible for the prenatal cocaine effect remain elusive. Using brains of the 21-day-old (P21) prenatal cocaine-exposed rats, we show that prenatal cocaine exposure uncouples mGluR1s from their associated synaptic anchoring protein, Homer1 and signal transducer, Gq/11 proteins leading to markedly reduced mGluR1-mediated phosphoinositide hydrolysis in frontal cortex (FCX) and hippocampus.

Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A.

PTI-125 is a novel compound demonstrating a promising new approach to treating Alzheimer's disease (AD), characterized by neurodegeneration and amyloid plaque and neurofibrillary pathologies. We show that the toxic signaling of amyloid-β(42) (Aβ(42)) by the α7-nicotinic acetylcholine receptor (α7nAChR), which results in tau phosphorylation and formation of neurofibrillary tangles, requires the recruitment of the scaffolding protein filamin A (FLNA). By binding FLNA with high affinity, PTI-125 prevents Aβ(42)'s toxic cascade, decreasing phospho-tau and Aβ aggregates and reducing the dysfunction of α7nAChRs, NMDARs, and insulin receptors.

Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹.

Prenatal cocaine exposure increases synaptic localization of a neuronal RasGEF, GRASP-1 via hyperphosphorylation of AMPAR anchoring protein, GRIP.

Prenatal cocaine exposure causes sustained phosphorylation of the synaptic anchoring protein, glutamate receptor interacting protein (GRIP1/2), preventing synaptic targeting of the GluR2/3-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs; J. Neurosci. 29: 6308-6319, 2009).

S 24795 limits beta-amyloid-alpha7 nicotinic receptor interaction and reduces Alzheimer's disease-like pathologies.

Background: Beta-amyloid (Abeta) enables Alzheimer's disease (AD) plaque and neurofibrillary pathogenesis. Soluble Abeta promotes intraneuronal Abeta aggregates and tau phosphorylation by interacting with alpha7 nicotinic receptors (alpha7nAChRs). The current study assessed whether the novel alpha7nAChR partial agonist 2-(2-(4-bromophenyl)-2-oxoethyl)-1-methyl pyridinium (S 24795) could reduce AD-like pathologies by interfering with Abeta-alpha7nAChR interaction.

Prenatal cocaine reduces AMPA receptor synaptic expression through hyperphosphorylation of the synaptic anchoring protein GRIP.

Prenatal cocaine exposure produces sustained neurobehavioral and brain synaptic changes closely resembling those of animals with defective AMPA receptors (AMPARs). We hypothesized that prenatal cocaine exposure attenuates AMPAR signaling by interfering with AMPAR synaptic targeting. AMPAR function is governed by receptor cycling on and off the synaptic membrane through its interaction with glutamate receptor-interacting protein (GRIP), a PDZ domain protein that is regulated by reversible phosphorylation.

Prenatal cocaine increases dendritic spine density in cortical and subcortical brain regions of the rat.

Alterations in dendritic spine density following prenatal cocaine exposure were examined in the present study. Timed pregnant rats were injected daily with 30 mg/kg cocaine or saline during gestation. At postnatal day 21, male and female animals were separated and spine density was assessed following Golgi impregnation.

Cannabinoid-induced tolerance is associated with a CB1 receptor G protein coupling switch that is prevented by ultra-low dose rimonabant.

The analgesic effect of opioids is enhanced, and tolerance is attenuated, by ultra-low doses (nanomolar to picomolar) of an opioid antagonist, an effect that is mediated by preventing the receptor from coupling to Gs proteins. Recently, we demonstrated a cannabinoid-opioid interaction at the ultra-low dose level, suggesting that the effect might not be specific to opioid receptors. The purpose of this study was to examine, both behaviorally and mechanistically, whether the cannabinoid CB1 receptor was also sensitive to ultra-low dose effects.

Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia.

Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor erbB in the pathophysiology of schizophrenia. Among NRG1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in the modulation of N-methyl-D-aspartate (NMDA) receptor signaling. Here, using a new postmortem tissue-stimulation approach, we show a marked increase in NRG1-induced activation of erbB4 in the prefrontal cortex in schizophrenia.

Regulation of cyclin-dependent kinase 5 and calcium/calmodulin-dependent protein kinase II by phosphatidylinositol-linked dopamine receptor in rat brain.

A brain dopamine receptor that modulates phosphatidylinositol (PI) metabolism via the activation of phospholipase Cbeta (PLCbeta) has been described previously. The present study aims to define the downstream signaling cascade initiated by the PI-linked dopamine receptor. Incubation of rat brain frontal cortical slices with 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959), a recently identified selective agonist of the PI-linked D1-like dopamine receptor, elicited transient time- and dose-dependent stimulations of cyclin-dependent kinase 5 (cdk5) and calcium/calmodulin-dependent protein kinase II (CaMK II) activities.