Alzheimer's Disease (AD) is the most common of the senile dementias, the prevalence of which is increasing rapidly, with a projected 14 million affected worldwide by 2025. The signal transduction mechanisms that underlie the learning and memory derangements in AD are poorly understood. ␤-Amyloid (A␤) peptides are elevated in brain tissue of AD patients and are the principal component of amyloid plaques, a major criterion for postmortem diagnosis of the disease. Using acute and organotypic hippocampal slice preparations, we demonstrate that A␤ peptide 1-42 (A␤42) couples to the mitogen-activated protein kinase (MAPK) cascade via ␣7 nicotinic acetylcholine receptors (nAChRs). In vivo elevation of A␤, such as that exhibited in an animal model for AD, leads to the upregulation of ␣7 nAChR protein. ␣7 nAChR upregulation occurs concomitantly with the downregulation of the 42 kDa isoform of extracellular signal-regulated kinase (ERK2) MAPK in hippocampi of aged animals. The phosphorylation state of a transcriptional mediator of long-term potentiation and a downstream target of the ERK MAPK cascade, the cAMP-regulatory element binding (CREB) protein, were affected also. These findings support the model that derangement of hippocampus signal transduction cascades in AD arises as a consequence of increased A␤ burden and chronic activation of the ERK MAPK cascade in an ␣7 nAChR-dependent manner that eventually leads to the downregulation of ERK2 MAPK and decreased phosphorylation of CREB protein.

The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor channels (nAChRs). These receptors are widely distributed throughout the central nervous system, being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in the mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer’s disease), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain.

Summary The activation of the N-methyl D-aspartate receptor (NMDAR) is controlled by a glutamate-binding site and a distinct, independently regulated, co-agonist-binding site. In most brain regions, the NMDAR co-agonist is the astrocyte-derived gliotransmitter D-serine. We found that D-serine levels oscillate in mouse hippocampus as a function of wakefulness, in vitro and in vivo. This causes a full saturation of the NMDAR co-agonist site in the dark (active)-phase that dissipates to sub-saturating levels during the light (sleep)-phase, and influences learning performance throughout the day. We demonstrate that hippocampal astrocytes sense the wakefulness-dependent activity of septal cholinergic fibers through the α7-nicotinic acetylcholine receptor (α7nAChR), whose activation drives D-serine release. We conclude that astrocytes tune the gating of synaptic NMDARs to the vigilance state and demonstrate that this is directly relevant to schizophrenia, a disorder characterized by NMDAR and cholinergic hypofunctions. Indeed, bypassing cholinergic activity with a clinically-tested α7nAChR agonist successfully enhances NMDARs activation.

The ␣7 nicotinic acetylcholine receptor is highly expressed in hippocampus and in cholinergic projection neurons from the basal forebrain, structures that are particularly vulnerable to the ravages of Alzheimer's disease. Previous work suggests that ␤-amyloid peptide can interact with ␣7 nicotinic acetylcholine receptors, although the nature of this interaction has not been well characterized. To test whether ␤-amyloid peptide can activate ␣7 nicotinic acetylcholine receptors, we expressed these receptors in Xenopus oocytes and performed two-electrode voltage clamp recordings, characterizing the response to ␤-amyloid peptide 1-42 applied at concentrations ranging from 1 pM to 100 nM. In ␣7-expressing oocytes, ␤-amyloid peptide 1-42 elicits inward currents at low concentrations (1-100 pM), whereas at higher concentrations (nM), less effective receptor activation is observed, indicative of receptor desensitization. Preincubation with the ␣7-selective agents, the antagonist methyllycaconatine, and the agonist 4-OH-GTS-21 blocked ␤-amyloid peptide-induced receptor activation. ␤-amyloid peptide 1-42 at low concentrations was able to activate the L250T mutant ␣7 receptor. The endogenous Ca 2؉ -activated chloride current in Xenopus oocytes is recruited upon receptor activation since replacing Ca 2؉ with Ba 2؉ in the recording solution reduced current amplitude. Thus, when ␤-amyloid peptide activation of ␣7 receptors occurs, these currents are comprised, at least in part, of Ca 2؉ .Alzheimer's Disease (AD) 1 is the most common of the senile dementias, the prevalence of which is increasing rapidly with a projected 14 million affected worldwide by 2025. Early on, AD presents clinically as impaired memory formation, yet despite intensive study, the mechanisms underlying AD-related memory dysfunction remain mysterious. Familial AD is associated with several risk factors, the best correlated being age and the inheritance of specific genes (mutations or allele type) that predominantly result in increased ␤-amyloid peptide (A␤) levels (1, 2, 33).Although these peptides are present in the brains and cerebrospinal fluid of normal subjects at the picomolar level, substantial evidence indicates that elevated A␤ is a culprit in the cognitive decline of AD (1). A␤ is generated from the amyloid precursor protein through endoproteolytic cleavage by ␤-and ␥-secretases (2). In normal individuals, A␤-(XϪ40) (A␤40) comprises the majority of the A␤ population; a far smaller fraction is made up of A␤42 (1). A␤42 is highly fibrillogenic and exhibits trophic and toxic effects on neurons (3-5). The hippocampus is a locus for the earliest detected cognitive dysfunction in AD: impairment in the encoding of new episodic memories is typical of the earliest stages of AD, and the loss of episodic memory in AD is linked to medial temporal pathology inclusive of the hippocampus (6 -8). Despite intensive study, the mechanism by which elevated A␤ leads to AD-related hippocampal dysfunction remains mysterious, not to mention the lack of an understanding ...

Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease (AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.

Familial Alzheimer's disease-associated mutations in presenilin 1 or 2 or amyloid precursor protein result in elevated ␤-amyloid, ␤-amyloid accumulation, and plaque formation in the brains of affected individuals. By crossing presenilin 1 transgenic mice carrying the A246E mutation with plaque-producing amyloid precursor protein K670N/M671L transgenic mice (Tg2576), we show that co-expression of both mutant transgenes results in acceleration of amyloid accumulation and associative learning deficits. At 5 months of age with no detectable plaque pathology, amyloid precursor protein transgenic animals are impaired in contextual fear learning following two pairings of conditioned and unconditioned stimuli but appear normal following a more robust five-pairing training. At 9 months of age when ␤-amyloid deposition is evident, these mice are impaired following both two-pairing and five-pairing protocols. Mice carrying both transgenes are impaired in contextual fear conditioning at either age. All transgenic animal groups performed as well as controls in cued fear conditioning, indicating that the contextual fear learning deficits are hippocampus-specific. The associative learning impairments are coincident with elevated ␣7 nicotinic acetylcholine receptor protein in the dentate gyrus. These findings provide two robust and rapid assays for ␤-amyloid-associated effects that can be performed on young animals: impaired contextual fear learning and up-regulation of ␣7 nicotinic receptors.Early on, Alzheimer's disease (AD) 1 presents clinically as impaired memory formation, yet despite intensive study the mechanisms underlying AD-related memory dysfunction remain mysterious. Familial AD (FAD) is associated with several risk factors, the best-correlated being age and the inheritance of specific genes (mutations or allele type) that result in increased ␤-amyloid (A␤) production. The discovery that soluble A␤ is elevated in the brains of AD patients raises the issue whether these molecules play a causative role in AD (1). A␤ is generated from the amyloid precursor protein (APP) through endoproteolytic cleavage by ␤-and ␥-secretases (2). In normal individuals, A␤40 comprises the majority of the A␤ population; a far smaller fraction is made up of A␤42 (1). A␤42 is highly fibrillogenic and exhibits trophic and toxic effects on neurons (3-5).Utilizing acute and organotypic hippocampal slice preparations, we have recently shown that A␤42 activates the mitogenactivated protein kinase (MAPK) cascade through ␣7 nicotinic acetylcholine receptors (␣7 nAChRs) (6). We also demonstrated that elevation of A␤ in vivo using an animal model for AD (Tg2576) (7), leads to the up-regulation of hippocampal ␣7 nAChR protein. ␣7 nAChR up-regulation in the hippocampus of Tg2576 animals negatively correlates with their performance in the Morris water maze, a hippocampus-dependent spatial learning task, and ␣7 nAChR up-regulation occurs concomitantly with dysregulation of the 42-kDa isoform of extracellular signal-regulated kinase (ERK2) MAPK (6). Cons...

Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer's disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1) M146V KI; Thy1.2-amyloid precursor protein (APP) swe ; Thy1.2tau P301L ] that develops AD-like plaques and tangles, as well as the double (PS1 M146V KI; Thy1.2-APP swe ) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid b peptide levels (Tg2576 and APP/amyloid b-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect. Keywords: Alzheimer's disease, collapsin response mediator protein 2, cyclin-dependent kinase 5, glycogen synthase kinase 3, phosphorylation.

Aberrant amyloid-β peptide (Aβ) accumulation along with altered expression and function of nicotinic acetylcholine receptors (nAChRs) stand prominently in the etiology of Alzheimer's disease (AD). Since the discovery that Aβ is bound to α7 nAChRs under many experimental settings, including post-mortem AD brain, much effort has been expended to understand the implications of this interaction in the disease milieu. This research update will review the current literature on the α7 nAChR-Aβ interaction in vitro and in vivo, the functional consequences of this interaction from sub-cellular to cognitive levels, and discuss the implications these relationships might have for AD therapies.