Faculty Bibliography

Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.

OBJECTIVE: To validate serum neutrophil gelatinase-associated lipocalin (NGAL) as an early biomarker for acute kidney injury in critically ill children with septic shock. DESIGN: Observational cohort study. SETTING: Fifteen North American pediatric intensive care units (PICUs). PATIENTS: A total of 143 critically ill children with systemic inflammatory response syndrome (SIRS) or septic shock and 25 healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum NGAL was measured during the first 24 hrs of admission to the PICU. Acute kidney injury was defined as a blood urea nitrogen concentration >100 mg/dL, serum creatinine >2 mg/dL in the absence of preexisting renal disease, or the need for dialysis. There was a significant difference in serum NGAL between healthy children (median 80 ng/mL, interquartile ratio [IQR] 55.5-85.5 ng/mL), critically ill children with SIRS (median 107.5 ng/mL, IQR 89-178.5 ng/mL), and critically ill children with septic shock (median 302 ng/mL, IQR 151-570 ng/mL; p < .001). Acute kidney injury developed in 22 of 143 (15.4%) critically ill children. Serum NGAL was significantly increased in critically ill children with acute kidney injury (median 355 ng/mL, IQR 166-1322 ng/mL) compared with those without acute kidney injury (median 186 ng/mL, IQR 98-365 ng/mL; p = .009). CONCLUSIONS: Serum NGAL is a highly sensitive but nonspecific predictor of acute kidney injury in critically ill children with septic shock. Further validation of serum NGAL as a biomarker of acute kidney injury in this population is warranted

Phosphodiesterases (PDEs) are enzymes that break down the phosphodiesteric bond of the cyclic nucleotides, cAMP and cGMP, second messengers that regulate many biological processes. PDEs participate in the regulation of signal transduction by means of a fine regulation of cyclic nucleotides so that the response to cell stimuli is both specific and activates the correct third messengers. Several PDE inhibitors have been developed and used as therapeutic agents because they increase cyclic nucleotide levels by blocking the PDE function. In particular, sildenafil, an inhibitor of PDE5, has been mainly used in the treatment of erectile dysfunction but is now also utilized against pulmonary hypertension. This review examines the physiological role of PDE5 in synaptic plasticity and memory and the use of PDE5 inhibitors as possible therapeutic agents against disorders of the central nervous system (CNS).

In this paper, we compare and validate different probabilistic models of human heart beat intervals for assessment of the electrocardiogram data recorded with varying conditions in posture and pharmacological autonomic blockade. The models are validated using the adaptive point process filtering paradigm and Kolmogorov-Smirnov test. The inverse Gaussian model was found to achieve the overall best performance in the analysis of autonomic control. We further improve the model by incorporating the respiratory covariate measurements and present dynamic respiratory sinus arrhythmia (RSA) analysis. Our results suggest the instantaneous RSA gain computed from our proposed model as a potential index of vagal control dynamics.

Examination of spontaneous intrinsic brain activity is drawing increasing interest, thus methods for such analyses are rapidly evolving. Here we describe a novel measure, 'network homogeneity', that allows for assessment of cohesiveness within a specified functional network, and apply it to resting-state fMRI data from adult ADHD and control participants. We examined the default mode network, a medial-wall based network characterized by high baseline activity that decreases during attention-demanding cognitive tasks. We found reduced network homogeneity within the default mode network in ADHD subjects compared to age-matched controls, particularly between the precuneus and other default mode network regions. This confirms previously published results using seed-based functional connectivity measures, and provides further evidence that altered precuneus connectivity is involved in the neuropathology of ADHD. Network homogeneity provides a potential alternative method for assessing functional connectivity of specific large-scale networks in clinical populations

We determined the nervous system targeting of interferon-beta1b (IFN-beta1b), a 20 kDa protein used to treat the relapsing-remitting form of multiple sclerosis, following intranasal administration in anesthetized, adult cynomolgus monkeys. Five animals received an intranasal bolus of [(125)I]-labeled IFN-beta1b, applied bilaterally to the upper nasal passages. Serial blood samples were collected for 45 min, after which the animals were euthanized by transcardial perfusion-fixation. High resolution phosphor imaging of tissue sections and gamma counting of microdissected tissue were used to obtain the distribution and concentration profiles of [(125)I]-IFN-beta1b in central and peripheral tissues. Intranasal administration resulted in rapid, widespread targeting of nervous tissue. The olfactory bulbs and trigeminal nerve exhibited [(125)I]-IFN-beta1b levels significantly greater than in peripheral organs and at least one order of magnitude higher than any other nervous tissue area sampled. The basal ganglia exhibited highest [(125)I]-IFN-beta1b levels among CNS regions other than the olfactory bulbs. Preferential IFN-beta1b distribution to the primate basal ganglia is a new finding of possible clinical importance. Our study suggests both IFN-beta and IFN-alpha, which share the same receptor, may be bound with relatively high affinity in these structures, possibly offering new insight into a neurovegetative syndrome induced by IFN-alpha therapy and suspected to involve altered dopamine neurotransmission in the basal ganglia. Most importantly, our results suggest intranasally applied macromolecules may bypass the blood-brain barrier and rapidly enter the primate CNS along olfactory- and trigeminal-associated extracellular pathways, as shown previously in the rat. This is the first study to finely detail the central distribution of a labeled protein after intranasal administration in non-human primates

Spike timing-dependent synaptic plasticity (STDP) plays an important role in neural development and information processing in the brain; however, the mechanism by which spike timing information is encoded into STDP remains unclear. Here, we show that a novel allosteric kinetics of NMDA receptors (NMDARs) is required for STDP. We developed a detailed biophysical model of STDP and found that the model required spike timing-dependent distinct suppression of NMDARs by Ca(2+)-calmodulin. This led us to predict an allosteric kinetics of NMDARs: a slow and rapid suppression of NMDARs by Ca(2+)-calmodulin with prespiking --> postspiking and postspiking --> prespiking, respectively. We found that the allosteric kinetics, but not the conventional kinetics, is consistent with specific features of amplitudes and peak time of NMDAR-mediated EPSPs in experiments. We found that the allosteric kinetics of NMDARs was also valid for synaptic plasticity induced by more complex spike trains in layer II/III of visual cortex. We extracted an essential synaptic learning rule by reduction of the allosteric STDP model and found that spike timing-dependent bidirectional role of postspiking in synaptic modification, which depends on the allosteric kinetics, is the essential principle in STDP. Thus, we propose a simple hypothesis of the allosteric kinetics of NMDARs that can coherently explain critical features of spike timing-dependent NMDAR-mediated EPSPs and synaptic plasticity

Soluble amyloid-beta (Abeta) peptide is likely to play a key role during early stages of Alzheimer's disease (AD) by perturbing synaptic function and cognitive processes. Receptor for advanced glycation end products (RAGE) has been identified as a receptor involved in Abeta-induced neuronal dysfunction. We investigated the role of neuronal RAGE in Abeta-induced synaptic dysfunction in the entorhinal cortex, an area of the brain important in memory processes that is affected early in AD. We found that soluble oligomeric Abeta peptide (Abeta42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, Abeta did not inhibit LTP in slices from RAGE-null mutant mice or in slices from wild-type mice treated with anti-RAGE IgG. Similarly, transgenic mice expressing a dominant-negative form of RAGE targeted to neurons showed normal LTP in the presence of Abeta, suggesting that neuronal RAGE functions as a signal transducer for Abeta-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by Abeta, we used inhibitors of stress activated kinases. We found that inhibiting p38 mitogen-activated protein kinase (p38 MAPK), but not blocking c-Jun N-terminal kinase activation, was capable of maintaining LTP in Abeta-treated slices. Moreover, Abeta-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that Abeta impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK

Whether motion vision uses color contrast is a controversial issue that has been investigated in several species, from insects to humans. We used Drosophila to answer this question, monitoring the optomotor response to moving color stimuli in WT and genetic variants. In the fly eye, a motion channel (outer photoreceptors R1-R6) and a color channel (inner photoreceptors R7 and R8) have been distinguished. With moving bars of alternating colors and high color contrast, a brightness ratio of the two colors can be found, at which the optomotor response is largely missing (point of equiluminance). Under these conditions, mutant flies lacking functional rhodopsin in R1-R6 cells do not respond at all. Furthermore, genetically eliminating the function of photoreceptors R7 and R8 neither alters the strength of the optomotor response nor shifts the point of equiluminance. We conclude that the color channel (R7/R8) does not contribute to motion detection as monitored by the optomotor response.

Glucocorticoids (GCs) display both protective and destructive effects in the nervous system. In excess, GCs produce neuronal damage after stress or brain injury; however, the neuroprotective effects of adrenal steroids also have been reported. The mechanisms that account for the positive actions are not well understood. Here we report that GCs can selectively activate Trk receptor tyrosine kinases after in vivo administration in the brain and in cultures of hippocampal and cortical neurons. Trk receptors are normally activated by neurotrophins, such as NGF and brain-derived neurotrophic factor, but the activation of Trk receptors by GCs does not depend on increased production of neurotrophins. Other tyrosine kinase receptors, such as EGF and FGF receptors, were not activated by GCs. The ability of GCs to increase Trk receptor activity resulted in the neuroprotection of neurons deprived of trophic support and could be modulated by steroid-converting enzymes. Pharmacological and shRNA experiments indicate that Trk receptor activation by GCs depends on a genomic action of the GC receptor. The ability of GCs to promote Trk receptor activity represents a molecular mechanism that integrates the actions of GCs and neurotrophins