α7 nicotinic acetylcholine receptors in Alzheimer's disease: neuroprotective, neurotrophic or both?

One of the early signs of Alzheimer's disease is the impairment in hippocampus-based episodic memory function, which is improved through the enhancement of cholinergic transmission. Several studies suggest that α7 nicotinic receptor (nAChR) activation represents a useful therapeutic strategy for the cognitive impairments associated with early Alzheimer's disease as the α7 subtype of nicotinic acetylcholine receptors are expressed by basal forebrain cholinergic projection neurons as well as by their targets in the hippocampus. The current model for the cholinergic deficit in Alzheimer's disease posits that inappropriate accumulation of misfolded oligomeric aggregates of β-amyloid peptide leads to the dysfunction of the signaling mechanisms that support the cholinergic phenotype; this is manifested as an altered function of nicotinic acetylcholine receptors and the nerve-growth factor trophic support system that results in the loss of cholinergic markers and eventually cholinergic neurons from the basal forebrain cholinergic system. A view was confounded by the fact that α7 nAChRs and β-amyloid peptides have been shown to interact in vitro and in vivo, including human post-mortem AD brain. This review will begin with a brief overview of the basal forebrain cholinergic system, followed by a discussion of the current knowledge of the cholinergic deficit in Alzheimer's disease, then a summary of the cholinergic phenotype observed in transgenic Alzheimer's disease mouse models. We will also present our recent findings that support our hypothesis that the α7 nicotinic acetylcholine receptor performs both the neurotrophic and neuroprotective roles in the maintenance of the cholinergic phenotype and discusses potential mechanisms and implications for Alzheimer's disease therapy.     

Cholinergic but not monoaminergic denervation increases nerve growth factor content in the adult rat hippocampus and cerebral cortex

Summary We have investigated whether degeneration of basal forebrain cholinergic neurons is a potential trigger for increased NGF production in the adult rat brain. Electrolytic lesions of cholinergic neurons in the septum-diagonal band and in the nucleus basalis of Meynert induced a transient increase in NGF in the ventral hippocampus (+70%) and cerebral cortex (+125%), respectively. In contrast, selective aminergic denervation of the forebrain by electrolytic lesion of the medial forebrain bundle, did not increase NGF levels in hippocampus and cerebral cortex. Thus, a cholinergic mechanism appears to regulate NGF production in adult rat basal forebrain.     

Nerve growth factor: structure, function and therapeutic implications for Alzheimer's disease

Over the past decade, neurotrophic factors have generated much excitement for their potential as therapy for neurological disorders. In this regard, nerve growth factor (NGF), the founding member of the neurotrophin family, has generated great interest as a potential target for the treatment of Alzheimer's disease (AD). This interest is based on the observation that cholinergic basal forebrain (CBF) neurons which provide the major source of cholinergic innervation to the cerebral cortex and hippocampus undergo selective and severe degeneration in advanced AD and that these neurons are dependent upon NGF and its receptors for their survival. In fact, NGF transduces its effects by binding two classes of cell surface receptors, TrkA and p75(NTR), both of which are produced by CBF neurons. This review focuses on NGF/receptor binding, signal transduction, regulation of specific cellular endpoints, and the potential use of NGF in AD. Alterations in NGF ligand and receptor expression at different stages of AD are summarized. Recent results suggest that cognitive deficits in early AD and mild cognitive impairment (MCI) are not associated with a cholinergic deficit. Thus, the earliest cognitive deficits in AD may involve brain changes other than simply cholinergic system dysfunction. Recent findings indicate an early defect in NGF receptor expression in CBF neurons; therefore treatments aimed at facilitating NGF actions may prove highly beneficial in counteracting the cholinergic dysfunction found in end-stage AD and attenuating the rate of degeneration of these cholinergic neurons.     

Mechanisms to prevent the toxicity of chronic neuroinflammation on forebrain cholinergic neurons

Inflammatory processes may play an important role in the degeneration of basal forebrain cholinergic cells Alzheimer's disease. We infused the proinflammagen lipopolysaccharide into the basal forebrain of young rats and determined whether the chronic administration of two novel non-steroidal anti-inflammatory drugs or a pan-caspase synthesis inhibitor, z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD), could provide neuroprotection from the cytotoxic effects of the neuroinflammation. Chronic lipopolysaccharide infusions decreased choline acetyltransferase activity and increased the number of activated microglia within the basal forebrain region. The level of caspases 3, 8 and 9 was increased in ventral caudate/putamen. Non-steroidal anti-inflammatory drug therapy attenuated the toxicity of the inflammation upon cholinergic cells and reduced caspases 3, 8 and 9 activity in the caudate/putamen. zVAD treatment significantly decreased the levels of caspases 3, 8 and 9 but did not provide neuroprotection for the cholinergic neurons. These results suggest that prostaglandins contribute to the degeneration of forebrain cholinergic neurons in Alzheimer's disease.     

神经生长因子治疗阿尔采末病的胆碱能神经机制

神经生长因子 (nervegrowthfactor,NGF)是中枢胆碱能神经元存活和功能维持最重要的神经营养因子之一 ,对阿尔采末病 (Alzheimersdisease,AD)的治疗潜力已引起人们极大兴趣。投射于大脑皮质和海马的基底前脑胆碱能神经元退变是AD早期病变 ,也是导致患者认知功能降低的主要原因。NGF可通过兴奋残存神经元上高亲和性TrkA受体 ,促进中枢胆碱能神经元的存活和正常功能的发挥 ,同时神经元激活也使其自身免受AD的有害作用 ,即所谓“useitorloseit”现象。然而 ,NGF不能透过血脑屏障 ,如何使外源性NGF到达脑内靶区是亟待解决的难题 ,一旦获得理论和技术上的突破 ,NGF防治AD的临床应用才更具价值     

Cholecystokinin protects cholinergic neurons against basal forebrain lesion.

Alzheimer's Disease (AD) patients have a severe degeneration of cholinergic neurons in their cerebral cortices. Basal forebrain (BF)-lesioned rat is used as a model animal of a cholinergic deficit in the cerebral cortex. Cholinergic markers were decreased in the cerebral cortex of BF-lesioned rats. Intracerebroventricular continuous infusion of cholecystokinin octapeptide (CCK8) following BF lesion obviously preserved these cholinergic markers. These results suggest that CCK8 prevents the degeneration of cholinergic neurons in the cerebral cortex following BF lesion.     

Muscarinic receptors in brain stem and mesopontine cholinergic arousal functions

All five muscarinic receptor subtypes and mRNAs are found widely in the brain stem, with M? muscarinic receptors most concentrated in the hindbrain. Three cholinergic cell groups, Ch5: pedunculopontine (PPT); Ch6: laterodorsal tegmental (LDT); Ch8: parabigeminal (PBG), are found in the tegmentum. Ch5,6 neurons are activated by arousing and reward-activating stimuli, and inhibited via M?-like autoreceptors. Ch5,6 ascending projections activate many forebrain regions, including thalamus, basal forebrain, and orexin/hypocretin neurons (via M? receptors) for waking arousal and attention. Ch5,6 activation of dopamine neurons of the ventral tegmental area and substantia nigra (via M? receptors) increases reward-seeking and energizes motor functions. M? receptors on dopamine neurons facilitate brain-stimulation reward, opiate rewards and locomotion, and male ultrasonic vocalizations during mating in rodents. Ch5 cholinergic activation of superior colliculus intermediate layers facilitates fast saccades and approach turns, accompanied by nicotinic and muscarinic inhibition of the startle reflex in pons. Ch8 PBG neurons project to the outer layers of the superior colliculus only, where M? receptors are associated with retinotectal terminals. Ch5,6 descending projections to dorsal pontine reticular formation contribute to M?-dependent REM sleep.     

Cholinergic Modulation of General Anesthesia

Acetylcholine in the brain promotes arousal and facilitates cognitive functions. Cholinergic neurons in the mesopontine brainstem and basal forebrain are important for activation of the cerebral cortex, which is characterized by the suppression of irregular slow waves, an increase in gamma (30-100 Hz) activity in the electroencephalogram, and the appearance of a hippocampal theta rhythm. During general anesthesia, a decrease in acetylcholine release and cholinergic functions contribute to the desired outcomes of general anesthesia, such as amnesia, loss of awareness and consciousness, and immobility. Animal experiments indicate that inactivation, lesion, or genetic ablation of cholinergic neurons in the basal forebrain potentiated the effects of inhalational and injectable anesthetics, including isoflurane, halothane, propofol, pentobarbital, and in some cases, ketamine. Increased behavioral sensitivity to general anesthesia, faster induction time, and delayed recovery of a loss of righting reflex have been observed in rodents with basal forebrain cholinergic deficits. Cholinergic stimulation in the prefrontal cortex, thalamus, and basal forebrain hastens recovery from general anesthesia. Anticholinesterase accelerates emergence from general anesthesia, but with mixed success, in part depending on the anesthetic used. Cholinergic deficits may contribute to cognitive impairments after anesthesia and operations, which are severe in aged subjects. We propose a cholinergic hypothesis for postoperative cognitive disorder, in line with the cholinergic deficits and cognitive decline in aging and Alzheimer’s disease. The current animal literature suggests that brain cholinergic neurons can regulate the immune and inflammatory response after surgical operation and anesthetic exposure, and anticholinesterase and α7-nicotinic cholinergic agonists can alleviate postoperative inflammatory response and cognitive deficits.     

囊泡谷氨酸转运体与神经系统疾病

囊泡谷氨酸转运体(vesicular glutamate transporters,VGLUTs)能特异地装载谷氨酸进入突触囊泡并促进释放,它包括3个成员,其中VGLUT1和VGLUT2是谷氨酸能神经元和它们轴突末端高度特异的标志,同时VGLUT1标志着皮质-皮质投射,VGLUT2标志着丘脑-皮层投射。而VGLUT3则会出现在胆碱能中间神经元、5-羟色胺能神经元、海马和皮层中GABA能中间神经元中。VGLUTs的异常会导致兴奋性神经递质谷氨酸的异常,从而诱发多种神经系统疾病。该文综述了VGLUTs的功能障碍与阿尔采末病(Alzheimer’sdisease,AD)、帕金森病(Parkinson’s disease,PD)、精神分裂症、抑郁症、癫痫、耳聋发病的关系的研究进展,为这些疾病的防治提供新的线索。     

3,4-Methylenedioxymethamphetamine enhances the release of acetylcholine in the prefrontal cortex and dorsal hippocampus of the rat

Rationale The neurochemical effects produced by acute administration of 3,4-methylenedioxymethamphetamine (MDMA) on the monoaminergic systems in the brain are well documented; however, there has been little consideration of the potential effects of MDMA on other neurotransmitter systems. Objective The present study was designed to investigate the acute effect of MDMA on cholinergic neurons by measuring acetylcholine (ACh) release in the medial prefrontal cortex (PFC) and dorsal hippocampus, terminal regions of cholinergic projection neurons originating in the basal forebrain. Methods In vivo microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ED) were used to assess the effects of MDMA on the extracellular concentration of ACh in the PFC and dorsal hippocampus of the rat. Results The systemic administration of MDMA (3–20 mg/kg, i.p.) resulted in an increased extracellular concentration of ACh in the PFC and dorsal hippocampus. Reverse dialysis of MDMA (100 μM) into the PFC and hippocampus also increased ACh release in these brain regions. Treatment with parachlorophenylalanine and α-methyl-para-tyrosine, inhibitors of serotonin (5-HT) and dopamine (DA) synthesis, respectively, significantly attenuated the release of ACh stimulated by MDMA in the PFC, but not in the dorsal hippocampus. Conclusions MDMA exerts a stimulatory effect on the release of ACh in the PFC and dorsal hippocampus in vivo, possibly by mechanisms localized within these brain regions. In addition, these results suggest that the MDMA-induced release of ACh in the PFC involves both serotonergic and dopaminergic mechanisms.     

Muscarinic cholinergic contribution to memory consolidation: with attention to involvement of the basolateral amygdala

The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. And degeneration of the cholinergic basal forebrain (CBF) neurons is a pronounced hallmark of Alzheimer's Disease (AD). However, CBF immunolesions as animal models of AD cholinergic degeneration have not replicated the robust memory deficits of nonselective excitotoxic lesions. The less studied cholinergic projections to the amygdala, which are affected in AD but unaffected by immunolesions, may be more important in memory storage than previously suspected. The sparing of these amygdalopetal projections may help explain the dissociation between excitotoxic and immunotoxic CBF lesions. The CBF projections to cortex have since been shown to be important for attentional processes, which may contribute indirectly to memory. Nonetheless, there are conditions under which their selective ablation produces clear memory deficits. For example, memory enhancement induced by posttraining basolateral amygdalar activation is ineffective when corticopetal cholinergic projections are lesioned. Moreover, posttraining cholinergic agonism enhances long-term memory. Such findings suggest that cholinergic innervation of the cortex may be particularly important during modulation of memory storage for stressful and/or arousing events. In concordance, mR agonism facilitates neuronal plasticity and can induce expression of memory-associated immediate early genes. The present article reviews the behavior, physiology and inducible genetic expression literatures which together suggest that the early CBF lesion data were not a red herring but rather that CBF projections not only to cortex but also to the amygdala may in fact have important neuromodulatory functions in memory consolidation processes.     

The cholinergic deficit in Alzheimer's disease: impact on cognition, behaviour and function

Although the neurodegeneration occurring in Alzheimer's disease (AD) affects multiple neurotransmitters, the cholinergic system has received the greatest attention. Acetylcholine (ACh) is fundamental to mnemonic function, assisting in the septal hippocampal pathway and facilitating cortical activation. One of the earliest pathological events in AD is the degeneration of ACh-synthesizing neurons in the subcortical nuclei of the human basal forebrain. Indeed, the loss of cholinergic function in AD is correlated with the density of histopathological markers of AD, the severity of cognitive dysfunction and disease duration. However, the precise mechanism by which the cholinergic system influences cognition, and behaviour, is unknown. Recent preliminary data from functional imaging and ligand-binding studies implicate a dynamic interaction between the nicotinic-muscarinic cholinergic receptor systems. The relatively preserved thalamic nicotinic system, compared with the dysfunctional cortical muscarinic system, may facilitate thalamocortical metabolic excitation in the failing AD brain. Thus, it is hypothesized that thalamic influence within frontal-subcortical circuits is augmented in AD patients who demonstrate a marked improvement to cholinesterase inhibitor therapy. Understanding the cholinergic basis of the cognitive, functional and behavioural deficits in AD, and the differential treatment response to various agents, will ultimately improve patient care and neuropharmacological insights. This paper reviews the current understanding of the cholinergic influence in cognition, behaviour and, as a result, function in AD patients.     

Pharmaceutical research strategies in Alzheimer's disease

The hypothesis that the symptomatology of Alzheimer's disease is attributable to loss of cortical cholinergic innervation is supported by post-mortem studies demonstrating both reduced choline acetyltransferase (CAT) activity and reduced high-affinity choline uptake (HAChT) in the cortex, and neuron cell loss in the basal forebrain nucleus basalis of Meynert. Cholinergic denervation occurs early in the course of the disease and correlates with the severity of cognitive impairment. Pharmaceutical research strategies based on the cholinergic hypothesis and focusing on the development of acetylcholine esterase inhibitors and muscarinic agonist will be discussed. An alternative hypothesis to explain the dementia of Alzheimer's disease is the glutamatergic hypothesis. This is based on postmortem evidence indicating loss of glutamate, reduced binding and uptake of the neuro-transmitter and loss of pyramidal cells in the cortex. The possibility of developing glutamatergic drugs for treating the symptomatology of Alzheimer's disease will be considered. Studies have also indicated that the cellular processes involved in Alzheimer's disease occur in non-neuronal cells as well as in the brain. The possibility that Alzheimer's disease is a systemic disease and that drugs can be developed to treat the disease process will be considered.     

Galanin: neurobiologic mechanisms and therapeutic potential for Alzheimer's disease

The neuropeptide galanin (GAL) is widely distributed in the mammalian CNS. Several lines of evidence suggest that GAL may play a critical role in cognitive processes such as memory and attention through an inhibitory modulation of cholinergic basal forebrain activity. Furthermore, GAL fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer's disease (AD). This suggests that GAL activity impacts cholinergic dysfunction in advanced AD. Pharmacological and in vitro autoradiographic studies indicate the presence of heterogeneous populations of GAL receptor (GALR) sites in the basal forebrain which bind GAL with both high and low affinity. Interestingly, we have recently observed that GALR binding sites increase in the anterior basal forebrain in late-stage AD. Three G protein-coupled GALRs have been identified to date that signal through a diverse array of effector pathways in vitro, including adenylyl cyclase inhibition and phospholipase C activation. The repertoire and distribution of GALR expression in the basal forebrain remains unknown, as does the nature of GAL and GALR plasticity in the AD basal forebrain. Recently, GAL knockout and overexpressing transgenic mice have been generated to facilitate our understanding of GAL activity in basal forebrain function. GAL knockout mice result in fewer cholinergic basal forebrain neurons and memory deficits. On the other hand, mice overexpressing GAL display hyperinnervation of basal forebrain and memory deficits. These data highlight the need to explore further the putative mechanisms by which GAL signaling might be beneficial or deleterious for cholinergic cell survival and activity within basal forebrain. This information will be critical to understanding whether pharmacological manipulation of GALRs would be effective for the amelioration of cognitive deficits in AD.     

Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons

The invariant characteristic features associated with Alzheimer's disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid beta (Abeta) peptide, intracellular neurofibrillary tangles containing hyper-phosphorylated tau protein and the loss of basal forebrain cholinergic neurons. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that in vivo accumulation of Abeta(1-42) may initiate the process of neurodegeneration observed in AD brains. However, the cause of degeneration of the basal forebrain cholinergic neurons and their association to Abeta peptides or phosphorylated tau protein have not been clearly established. In the present study, using rat primary septal cultures, we have shown that Abeta(1-42), in a time (1-48 h) and concentration (0.01-20 microM)-dependent manner, induce toxicity in cultured neurons. Subsequently, we have demonstrated that Abeta toxicity is mediated via activation of cysteine proteases, i.e., calpain and caspase, and proteolytic breakdown of their downstream substrates tau, microtubule-associated protein-2 and alpha II-spectrin. Additionally, Abeta-treatment was found to induce phosphorylation of tau protein along with decreased levels of phospho-Akt and phospho-Ser(9)glycogen synthase kinase-3beta. Exposure to specific inhibitors of caspase or calpain can partially protect cultured neurons against Abeta-induced toxicity but their effects are not found to be additive. These results, taken together, suggest that Abeta peptide can induce toxicity in rat septal cultured neurons by activating multiple intracellular signaling molecules. Additionally, evidence that inhibitors of caspase and calpains can partially protect the cultured basal forebrain neurons raised the possibility that their inhibitors could be of therapeutic relevance in the treatment of AD pathology.     

Galactose counteracts hypoglycemia-induced decline of cholinergic neurons at low pH in organotypic rat brain slices of the basal nucleus of Meynert

A growing body of evidence indicates that hypoglycemia and acidosis may contribute to the development of Alzheimer's disease (AD). The cell death of basal forebrain cholinergic neurons constitutes a hallmark of AD and directly correlates with cognitive impairment. The aim of the present study was to investigate, in an organotypic rat brain slice model of the basal nucleus of Meynert, the effects of glucose deprivation on cholinergic neurons under normal and acidic conditions. Furthermore, we were interested to explore whether different saccharides (galactose, fructose, saccharose, lactose) can replace glucose under low pH conditions. Our data show a pH-dependent survival of cholinergic neurons at a high (37.1 mmol/l) glucose level, which was markedly decreased at a low (5.6 mmol/l) glucose level. Galactose (+31.5 mmol/l) significantly counteracted the loss of choline acetyltransferase-positive neurons in low-glucose-treated slices, while fructose, lactose and saccharose only partly protected cholinergic neurons. In conclusion, our results indicate that replacement of glucose with different saccharides, but most potently with galactose, protects cholinergic neurons against hypoglycemia at a low pH.     

Systemic and intrabasalis administration of the orexin-1 receptor antagonist,SB-334867, disrupts attentional performance in rats

Rationale  

Orexin neurons project to a number of brain regions, including onto basal forebrain cholinergic neurons. Basal forebrain corticopetal cholinergic neurons are known to be necessary for normal attentional performance. Thus, the orexin system may contribute to attentional processing.     

Sustained effect of metrifonate on cerebral glucose metabolism after immunolesion of basal forebrain cholinergic neurons in rats

To evaluate the influence of cholinergic projections from the basal forebrain on brain metabolism, we measured the cerebral metabolic rate of glucose (CMR(glu)) after unilateral lesioning of cholinergic basal forebrain neurons with the immunotoxin 192 IgG-saporin. CMR(glu) was determined in 24 cortical and 13 sub-cortical regions using the [14C]2-deoxy-D-glucose technique of Sokoloff. Average hemispheric CMR(glu) decreased by 7% (P<0.02) and 5% (P<0.05), 7 and 21 days after lesion, respectively. Regional effects were restricted to parietal and retrosplenial cortices, lateral habenula and the basal forebrain. We have previously shown that metrifonate increased CMR(glu) in intact rats. In lesioned rats, metrifonate (80 mg/kg, i. p.) was still active but the metabolic activation was reduced in terms of both the average hemispheric CMR(glu) and the number of regions significantly affected. Although it is reduced, the sustained effect of metrifonate in lesioned rats makes an argument for the use of this compound as treatment of cholinergic deficit in Alzheimer's disease.     

Cholinergic function in the aged brain: implications for treatment of memory impairments associated with aging

The cholinergic hypothesis of impaired memory in Alzheimer's disease has stimulated interest in cholinergic function of the brain in relation to the more common and less serious impairments of memory associated with normal (non-disease) aging. Unlike Alzheimer's disease, it is not clear whether normal aging results in a loss of cholinergic innervation to cerebral cortex and hippocampus, but prevailing evidence suggests that certain aspects of brain cholinergic function are diminished with advancing age. Human and animal data on the effects of aging on cholinergic systems of the brain are reviewed and are discussed in connection with the role these effects may play in the etiology and treatment of the learning and memory impairments associated with aging.     

Neuronal nicotinic acetylcholine receptors serve as sensitive targets that mediate β-amyloid neurotoxicity

Alzheimer's disease (AD) is the most common form of brain dementia characterized by the accumulation of beta-amyloid peptides (Abeta) and loss of forebrain cholinergic neurons. Abeta accumulation and aggregation are thought to contribute to cholinergic neuronal degeneration, in turn causing learning and memory deficits, but the specific targets that mediate Abeta neurotoxicity remain elusive. Recently, accumulating lines of evidence have demonstrated that Abeta directly modulates the function of neuronal nicotinic acetylcholine receptors (nAChRs), which leads to the new hypothesis that neuronal nAChRs may serve as important targets that mediate Abeta neurotoxicity. In this review, we summarize current studies performed in our laboratory and in others to address the question of how Abeta modulates neuronal nAChRs, especially nAChR subunit function.