Basic Science and Pathogenesis.

Background: Agora (https://agora.adknowledgeportal.org) is an openly available web resource developed to enable a broad spectrum of Alzheimer's disease (AD) researchers access to target-based evidence generated within the translational research portfolio of the National Institute on Aging (NIA).

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) therapeutics have largely been unsuccessful in alleviating disease burden in those afflicted by the disease. The TREAT-AD Consortium is an international group of academic researchers dedicated to identifying novel molecular targets for AD from underexplored areas of disease linked pathology.

Method: Utilizing a top-down expert curation approach of organizing Gene Ontology terms into endophenotypes of AD, we developed 19 biological domains.

Open drug discovery in Alzheimer's disease.

Alzheimer's disease (AD) drug discovery has focused on a set of highly studied therapeutic hypotheses, with limited success. The heterogeneous nature of AD processes suggests that a more diverse, systems-integrated strategy may identify new therapeutic hypotheses. Although many target hypotheses have arisen from systems-level modeling of human disease, in practice and for many reasons, it has proven challenging to translate them into drug discovery pipelines.

Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation.

Facilitation and inactivation of P/Q-type Ca2+ currents mediated by Ca2+/calmodulin binding to Ca(V)2.1 channels contribute to facilitation and rapid depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin from its binding site and differentially modulate P/Q-type Ca2 + currents, resulting in diverse patterns of short-term synaptic plasticity.

Patient-specific abutments for anterior maxillary implants.

Many factors influence the long-term functional and esthetic success of implant-supported restorations. This article reviews recent findings related to several of these factors, including the implant-abutment junction, bacterial adhesion to implant surfaces, and the esthetic and functional consequences of implant and abutment material choices, particularly titanium-nitride-coated abutments. Restoration of a failed maxillary central incisor using a platformswitched implant and titanium-nitride-coated abutment is presented.

Calcium channels and short-term synaptic plasticity.

Voltage-gated Ca(2+) channels in presynaptic nerve terminals initiate neurotransmitter release in response to depolarization by action potentials from the nerve axon. The strength of synaptic transmission is dependent on the third to fourth power of Ca(2+) entry, placing the Ca(2+) channels in a unique position for regulation of synaptic strength. Short-term synaptic plasticity regulates the strength of neurotransmission through facilitation and depression on the millisecond time scale and plays a key role in encoding information in the nervous system.

Fine-tuning synaptic plasticity by modulation of Ca(V)2.1 channels with Ca2+ sensor proteins.

Modulation of P/Q-type Ca(2+) currents through presynaptic voltage-gated calcium channels (Ca(V)2.1) by binding of Ca(2+)/calmodulin contributes to short-term synaptic plasticity. Ca(2+)-binding protein-1 (CaBP1) and Visinin-like protein-2 (VILIP-2) are neurospecific calmodulin-like Ca(2+) sensor proteins that differentially modulate Ca(V)2.

Modulation of high-voltage activated Ca(2+) channels by membrane phosphatidylinositol 4,5-bisphosphate.

Modulation of voltage-gated Ca(2+) channels controls activities of excitable cells. We show that high-voltage activated Ca(2+) channels are regulated by membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) with different sensitivities. Plasma membrane PIP(2) depletion by rapamycin-induced translocation of an inositol lipid 5-phosphatase or by a voltage-sensitive 5-phosphatase (VSP) suppresses Ca(V)1.

Direct enhancement of presynaptic calcium influx in presynaptic facilitation at Aplysia sensorimotor synapses.

Regulation of synaptic transmission by modulation of the calcium influx that triggers transmitter release underlies different forms of synaptic plasticity, and thus could contribute to learning. In the mollusk Aplysia, the neuromodulator serotonin (5-HT) increases evoked transmitter release from sensory neurons and thereby contributes to dishabituation and sensitization of defensive reflexes. We combined electrophysiological recording with fluorescence measurements of intracellular calcium in sensory neuron synapses in culture to test whether direct up-modulation by 5-HT of calcium influx triggered by single action potentials contributes to facilitation of transmitter release.

Isoform specificity of PKC translocation in living Aplysia sensory neurons and a role for Ca2+-dependent PKC APL I in the induction of intermediate-term facilitation.

Protein kinase Cs (PKCs) are important effectors of synaptic plasticity. In Aplysia, there are two major phorbol ester-activated PKCs, Ca2+-activated PKC Apl I and Ca2+-independent PKC Apl II. Functional Apl II, but not Apl I, in sensory neurons is required for a form of short-term facilitation induced at sensorimotor synapses by the facilitatory transmitter serotonin (5-HT).