Faculty Bibliography

The gene encoding the dipeptidyl peptidase-like protein DPP6 (also known as DPPX) has been associated with human neural disease. However, until recently no function had been found for this protein. It has been proposed that DPP6 is an auxiliary subunit of neuronal Kv4 K(+) channels, the ion channels responsible for the somato-dendritic A-type K(+) current, an ionic current with crucial roles in the regulation of firing frequency, dendritic integration and synaptic plasticity. This view has been supported mainly by studies showing that DPP6 is necessary to generate channels with biophysical properties resembling the native channels in some neurons. However, independent evidence that DPP6 is a component of neuronal Kv4 channels in the brain, and whether this protein has other functions in the CNS is still lacking. We generated antibodies to DPP6 proteins to compare their distribution in brain with that of the Kv4 pore-forming subunits. DPP6 proteins were prominently expressed in neuronal populations expressing Kv4.2 proteins and both types of protein were enriched in the dendrites of these cells, strongly supporting the hypothesis that DPP6 is an associated protein of Kv4 channels in brain neurons. The observed similarity in the cellular and subcellular patterns of expression of both proteins suggests that this is the main function of DPP6 in brain. However, we also found that DPP6 antibodies intensely labeled the hippocampal mossy fiber axons, which lack Kv4 proteins, suggesting that DPP6 proteins may have additional, Kv4-unrelated functions

The p75 neurotrophin receptor (p75(NTR)) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75(NTR) ligands found to promote survival signaling might prevent Abeta-induced degeneration and synaptic dysfunction. These ligands inhibited Abeta-induced neuritic dystrophy, death of cultured neurons and Abeta-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Abeta-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3beta and c-Jun, and tau phosphorylation, and prevented Abeta-induced inactivation of AKT and CREB. Finally, a p75(NTR) ligand blocked Abeta-induced hippocampal LTP impairment. These studies support an extensive intersection between p75(NTR) signaling and Abeta pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Abeta-induced neuronal dystrophy and death

The present invention relates to synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta which can be used alone or conjugated to an immunostimulatory molecule in an immunizing composition for inducing an immune response to amyloid beta peptides and amyloid deposits

This paper presents a series of experiments, both in patients and computer models, investigating the transition from acute to chronic hypercapnia in OSA. The data demonstrate that acute hypercapnia during periodic breathing occurs due to either reduction in magnitude of inter-event ventilation and/or reduction in inter-event ventilatory duration relative to duration of the preceding event. The transition between acute hypercapnia during sleep and chronic sustained hypercapnia during wakefulness may be determined by an interaction between respiratory control and renal handling of HCO3-.

RNA amplification is a series of molecular manipulations designed to amplify genetic signals from small quantities of starting materials (including single cells and homogeneous populations of individual cell types) for microarray analysis and other downstream genetic methodologies. A novel methodology named terminal continuation (TC) RNA amplification has been developed in this laboratory to amplify RNA from minute amounts of starting material. Briefly, an RNA synthesis promoter is attached to the 3' and/or 5' region of cDNA utilizing the TC mechanism. The orientation of amplified RNAs is 'antisense' or a novel 'sense' orientation. TC RNA amplification is utilized for many downstream applications, including gene expression profiling, microarray analysis, and cDNA library/subtraction library construction. Input sources of RNA can originate from a myriad of in vivo and in vitro tissue sources. Moreover, a variety of fixations can be employed, and tissues can be processed for histochemistry or immunocytochemistry prior to microdissection for TC RNA amplification, allowing for tremendous cell type and tissue specificity of downstream genetic applications