Alzheimer's disease produces a devastating decline in mental function, with profound effects on learning and memory. Early consequences of the disease include the specific loss of cholinergic neurons in brain, diminished cholinergic signaling, and the accumulation of ␤-amyloid peptide in neuritic plaques. Of the nicotinic acetylcholine receptors at risk, the most critical may be those containing the ␣7 gene product (␣7-nAChRs), because they are widespread, have a high relative permeability to calcium, and regulate numerous cellular events in the nervous system. With the use of whole-cell patch-clamp recording we show here that nanomolar concentrations of ␤-amyloid peptides specifically and reversibly block ␣7-nAChRs on rat hippocampal neurons in culture. The block is noncompetitive, voltage-independent, and use-independent and is mediated through the N-terminal extracellular domain of the receptor. It does not appear to require either calcium influx or G protein activation. ␤-Amyloid blockade is likely to be a common feature of ␣7-nAChRs because it applies to the receptors at both somato-dendritic and presynaptic locations on rat hippocampal neurons and extends to homologous receptors on chick ciliary ganglion neurons as well. Because ␣7-nAChRs in the central nervous system are thought to have numerous functions and recently have been implicated in learning and memory, impaired receptor function in this case may contribute to cognitive deficits associated with Alzheimer's disease. Alzheimer's disease is the most common form of dementia among the elderly, causing severe impairment of learning and memory; death usually occurs within 10 years after the onset of clinical symptoms (1, 2). Early cellular and molecular correlates of the disease include the accumulation of ␤-amyloid 40-and 42-aa peptides (A␤ 1-40 and A␤ 1-42 , respectively) in neuritic plaques (2, 3), loss of cholinergic neurons, and accompanying degeneration of cholinergic innervation (4-6). Although most studies of cholinergic deficits in Alzheimer's disease have focused on muscarinic aspects, diminished nicotinic transmission may be an important dimension as well because of reduced acetylcholine (ACh) levels and declines in the numbers of nicotinic acetylcholine receptors (nAChRs) in affected tissues (7-10).One of the most widely expressed nicotinic receptors in the nervous system is a species containing the ␣7 gene product (11,12). Such receptors (␣7-nAChRs) have an unusually high relative permeability to calcium and regulate numerous calciumdependent events in the nervous system (13,14). Examples include transmitter release (15, 16), second messenger cascades (17), neurite extension (18, 19), and both apoptosis (20) and neuronal survival (21). The receptors can also contribute directly to postsynaptic currents (22-24) and are expressed both at somato-dendritic and presynaptic sites on neurons in the hippocampus (16, 25-27), a structure critical for memory formation (28). Activation of ␣7-nAChRs can promote long-term potentiation at glutamatergic sy...

We report across-bandgap p-type and n-type control over the Seebeck coefficients of semiconducting single-wall carbon nanotube networks through an electric double layer transistor setup using an ionic liquid as the electrolyte. All-around gating characteristics by electric double layer formation upon the surface of the nanotubes enabled the tuning of the Seebeck coefficient of the nanotube networks by the shift in gate voltage, which opened the path to Fermi-level-controlled three-dimensional thermoelectric devices composed of one-dimensional nanomaterials.

Soluble amyloid ␤ oligomers (A␤Os) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying A␤O synaptic targeting is not known. Here, we show that the accumulation of synthetic or native Alzheimer's disease (AD)-brain oligomers at synapses is regulated by synaptic activity. Electrical or chemical stimulation increased A␤O synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked A␤O synaptic localization and reduced A␤O synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced A␤O synaptic targeting, which was also reduced in brain sections of animals deficient in the synaptic vesicle zinc transporter ZnT3, indicating that vesicular zinc released during neurotransmission is critical for A␤O synaptic targeting. Oligomers were not internalized in recycled vesicles but remained at the cell surface, where they colocalized with NR2B NMDA receptor subunits. Furthermore, NMDA antagonists blocked A␤O synaptic targeting, implicating excitatory receptor activity in oligomer formation and accumulation at synapses. In AD brains, oligomers of different size colocalized with synaptic markers in hippocampus and cortex, where oligomer synaptic accumulation correlated with synaptic loss.

Nicotinic acetylcholine receptors containing the alpha7 gene product are expressed at substantial levels in the hippocampus. Because of their specific locations and their high relative calcium permeability, the receptors not only mediate cholinergic transmission in the hippocampus but also influence signaling at noncholinergic synapses. We have used fluorescently labeled alpha-bungarotoxin to image alpha7-containing receptors on hippocampal neurons and to examine their regulation in culture. The highest levels of staining for such receptors were most commonly found on GABAergic interneurons identified immunohistochemically. The receptors were distributed in clusters on the soma and dendrites and were localized in part at GABAergic synapses. A 3 d blockade of electrical activity with tetrodotoxin or NMDA receptors with APV dramatically reduced the proportion of GABAergic neurons expressing high levels of receptor staining and reduced the mean number of distinguishable receptor clusters on individual neurons. Blockade of either GABA(A) receptors with bicuculline or nicotinic receptors with d-tubocurarine had no effect, although exposure to nicotine could increase the level of receptor staining. Anti-BDNF and anti-NGF antibodies produced decrements equivalent to those of tetrodotoxin and APV, whereas addition of BDNF and NGF each increased staining levels and increased the number of distinguishable receptor clusters on GABAergic neurons. The exogenous neurotrophins could not, however, overcome the effects of either tetrodotoxin or APV. The results indicate that both NMDA receptor activation and the neurotrophins BDNF and NGF are necessary to sustain the distribution patterns of alpha7-containing nicotinic receptors on GABAergic hippocampal neurons.

The thalamocortical pathway, a bundle of myelinated axons that arises from thalamic relay neurons, carries sensory information to the neocortex. Because axon excitation is an obligatory step in the relay of information from the thalamus to the cortex, it represents a potential point of control. We now show that, in adult mice, the activation of nicotinic acetylcholine receptors (nAChRs) in the initial portion of the auditory thalamocortical pathway modulates thalamocortical transmission of information by regulating axon excitability. Exogenous nicotine enhanced the probability and synchrony of evoked action potential discharges along thalamocortical axons in vitro, but had little effect on synaptic release mechanisms. In vivo, the blockade of nAChRs in the thalamocortical pathway reduced sound-evoked cortical responses, especially those evoked by sounds near the acoustic threshold. These data indicate that endogenous acetylcholine activates nAChRs in the thalamocortical pathway to lower the threshold for thalamocortical transmission and to increase the magnitude of sensory-evoked cortical responses. Our results show that a neurotransmitter can modulate sensory processing by regulating conduction along myelinated thalamocortical axons.