摘要:

Neurons in the central nervous system communicate almost exclusively by the production and release at synapses of a series of molecules that are designated transmitters. Three such molecules make up the major transmitters, GABA, glutamate, and acetylcholine. GABA neurons are the principal inhibitory neurons and, as such, are the major local circuit neurons of the brain. They also are projection neurons in a number of systems. Glutamate neurons are excitatory projection neurons, particularly of the cerebral cortex, thalamus and retina. Acetylcholine neurons are excitatory neurons in ascending brainstem and basal forebrain systems and in cranial and spinal motor neurons and neurons of the sympathetic and parasympathetic systems. The catecholamines, dopamine and norepinephrine, are transmitters in several systems in brain. Dopamine is present in midbrain neurons projecting to the neostriatum, basal forebrain and cerebral cortex. It is also produced by hypothalamic neurons projecting to the median eminence and pituitary. These systems are highly topographically organized in contrast to the norepinephrine systems. The locus coeruleus norepinephrine system projects principally to thalamus, cerebral cortex and cerebellar cortex whereas the lateral tegmental system projects primarily to basal forebrain, hypothalamus, brainstem and spinal cord. The serotonin neurons of the brainstem raphe also project widely over the neuraxis, midbrain raphe neurons primarily to diencephalon and telencephalon and pontine medullary neurons to brainstem and spinal cord. There are smaller neuronal groups that produce glycine or histamine.At the present time, it appears that most, if not all, CNS neurons produce one of these small molecule transmitters. In many instances, these molecules are colocalized with one or more peptides that appear to modify the postsynaptic action of the small molecule transmitter.

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23018.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The past decade has witnessed an enormous increase in our knowledge of the variety and complexity of intracellular signaling events that follow receptor binding on the cell surface. This overview emphasizes the phosphoinositidase C‐mediated dual messenger pathway in brain and in brain‐derived cells, with special reference to possible significance for research on the dement

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23019.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Five subtypes of muscarinic acetylcholine receptors have been identified and designated m1‐m5. The m1 and m3 receptors have recently been shown to stimulate APP processing. The m1 and m3 receptors couple to a variety of signal transduction pathways in both tissue slices and a variety of cell lines endogenously expressing either or both subtypes. In contrast, the m2 and m4 receptors have been primarily associated with inhibition of adenylate cyclase. We have transfected all five subtypes of muscarinic receptors into a variety of mammalian cell lines in order to investigate the signaling associated with single receptor subtypes. The m1, m3, or m5 receptors stimulate phospholipase A2, C, and D, adenylate cylase, receptor‐operated calcium channels, and tyrosine kinase activity simultaneously. The m2 or m4 receptor inhibits cAMP accumulation and augments a previously stimulated release of arachidonic acid and calcium inf

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23020.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

A substantial loss of cortical cholinergic nerve endings, along with a much more circumscribed cortical degeneration of pyramidal neurons, almost certainly causes glutamatergic hypoactivity in live Alzheimer's patients. Theseselectivepathologies are discussed in terms of therapy. An additional effect of some proposed treatments is emerging as there is evidence that processing pathways for β‐amyloid precursor proteins in cortical pyramidal neurons, a target cell for acetylcholine, are affected by neuronal activi

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23021.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Alzheimer's disease (AD) is characterized by multiple deficits of neurotransmitters in brain. These observations are mainly based upon studies in postmortem brain material where the disease has reached a terminal state. In order to obtain further insight into the early disturbances of the neurotransmitter activities in AD, new imaging techniques such as positron emission tomography (PET) and single positron emission tomography (SPECT) can be appliedin vivofor detection of neurotransmitter activity in normal as well as AD brains. Nicotinic receptors have been traced in AD patients by PET and11C‐nicotine at different stages of AD. A lower uptake of (R)(+)‐compared to (S)(‐)‐11C‐nicotine was observed in AD patients while the difference in uptake of the two enantiomeres was less pronounced in normal individuals. A positive correlation has been observed between cognitive function (Mini‐Mental‐State‐Examination) and uptake of (S)(‐)‐11C‐nicotine in the temporal cortex of AD patients.11C‐benztropine has been used to measure muscarinic receptors in brain by PET. Oral tacrine treatment (80 mg daily) restore nicotinic receptors in AD patients as visualized by PET and11C‐nicotine. Kinetic analysis indicate increased binding of (S)(‐)‐11C‐nicotine after 3 months of treatment with tacrine. The PET data are paralleled by improvement in neuropsychological testings. Intraventricular infusion of nerve growth factor (NGF) to an AD patients for 3 months resulted in an transient increase in uptake and binding of (S)(‐)‐11C‐nicotine in the temporal and frontal cortex and a persi

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23022.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

A compromise or deregulation in signal transduction cascades could adversely affect cellular functions and possibly contribute to cell death. In recent years, it has become increasingly apparent that pronounced activation of neuronal signal transduction systems is a characteristic of AD brain. There is evidence that signal transduction systems play a role in the formation or development of these pathological features of AD. Aberrant activity and localization of components of signaling mechanisms (growth factors, their receptors, protein kinases, phosphoprotein phosphatases, and phosphoproteins) are closely associated with the intracellular accumulation of PHF, the extracellular deposition of amyloid, and the formation of neuritic plaques in AD brain. In particular, immunohistochemical studies reveal increased levels of neuronal staining for APP, possibly an important growth factor in AD, both in frontal cortex and hippocampus. Anti‐APP immunostaining is also associated with the neuritic component of plaques. Additionally, PKC(βII) immunostaining is increased in the neuronal cell body and neuropil of AD samples, particularly in association with plaques, suggesting a postsynaptic involvement of this enzyme. On the other hand, PKC(βI) immunostaining is associated with axonal staining particularly in the sprouting neurites of plaques. Sprouting neuritic components of plaques are immunopositive with other growth‐associated proteins, such as GAP43, MARCKS, and spectrin. Immunoreactivity of other members of signal transduction systems such as Fos and stathmin are all increased in AD hippocampal neurons. On the other hand, several protein kinases and phosphoproteins were immunolocalized to tangles. Thus, the hyperactivation and dysfunction of signal transduction systems could be involved in the pathogenesis

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23023.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Previous reports have shown that there are age‐related reductions in muscarinic receptor (mAChR) sensitivity to agonist stimulation. Our research has elucidated the mechanisms involved in this loss. These studies have shown that this decline is the result of decreases in mAChR concentration, reductions in the number of neuronal cells, and altered phosphoinositide (PI)‐mediated signal transduction (ST). The decrements in PI‐mediated ST are observed as a reduced ability of muscarinic (m) agonists to enhance K+‐evoked release of DA (K+ERDA) from striatal slices from old rats. Additional experiments indicated that the locus of the ST deficits appears to be at the mAChR‐G protein interface, since attempts to bypass this interface reduced m‐enhanced K+ERDA deficits in the striata from old rats. Moreover, it appears that the ability of mAChR to decouple from their respective G proteins is reduced as a function of age, since carbachol‐stimulated low KMGTPase activity was found to be reduced in hippocampal and striatal tissue obtained from old rats. Similar findings were observed in this parameter in AD hippocampus and basal ganglia. Further reductions were seen in carbachol‐stimulated low KMGTPase as a function of the duration of the disease. Results are discussed in terms of structural membrane alterations in aging and disease that may lead to reductions in the efficacy of receptor‐G protein co

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23024.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Since phosphoinositide‐specific phospholipase C (PLC) is one of the key molecules in signal transduction, its involvement was assessed in Alzheimer's disease (AD). The phosphatidyl‐inositol (PI)‐specific PLC activity in the Alzheimer cytosolic and participate fractions was not significantly different from that in the control fractions. The PI‐specific PLC activity as a function of the free Ca2+concentration was also similar between control and Alzheimer brains. These results suggest that the PI‐specific PLC activity is not altered in AD. Immunostaining of a specific antibody against the PLC isozyme, PLC‐δ, demonstrated that this enzyme was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores, and neuropil threads in AD brains. Western blot analysis confirmed that PLC‐δ was concentrated in the paired helical filament (PHF)‐rich fraction of AD brains. PLC‐δ marked the same neurons containing τ immunoreactivity and yet τ and PLC‐δ often marked different structures within the same neuron, with τ more clearly on NFT and PLC‐δ covering it superficially. The double stain with PLC‐δ and basic fibroblast growth factor (bFGF) binding suggest that PLC‐δ is an intracellular marker, showing little overlap with bFGF binding, an extracellular marker. All of this was consistent with the electron microscopy, with PLC‐δ being NFT associated. Antibodies to other PLC isozymes did not produce positive immunostaining of these pathologic structures. Moreover, diffuse and amorphous deposits of PLC‐δ were found to precede the accumulation of fibrillary deposits. These results suggest that PLC‐δ accumulation plays a possible role in the

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23025.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The status of NMDA receptors in the brains of normal aged individuals and those with Alzheimer's disease was investigated. The binding of [3H]3‐((±)‐2‐carboxypiperazin‐4‐yl)propyl phosphonic acid ([3H]CPP) to NMDA antagonist‐preferring sites on frontal and temporal cortical synaptic membranes was assessed. Binding could be resolved into two components, one of high and the other of low affinity. Pharmacologically, the two sites were qualitatively similar. Considerable intersubject variation in binding parameters was detected, but no significant differences were found between the mean values for the control and Alzheimer's disease groups. This study indicates that, when changes in receptor integrity occur in individual patients, these may be occluded because of the large variations between

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23026.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Small angle x‐ray diffraction analysis of Alzheimer's disease (AD) lipid membranes reconstituted from cortical gray matter showed significant, reproducible structure changes relative to age‐matched control samples.1Specifically, there was an average 4 Å reduction in the lipid bilayer width and marked changes in membrane electron density profiles of AD cortical samples. There were no significant structure differences in the membrane bilayers isolated from an unaffected region (cerebellum) of the AD brain. Lipid and protein analysis of six AD and six age‐matched controls showed that the phospholipid : protein mass ratio was unchanged, but that the unesterified chlolesterol : phospholipid (C : PL) mole ratio decreased by 30% in the AD temporal gyrus relative to age‐matched controls. The C : PL mole ratio was not significantly different for samples prepared from cerebellum of AD versus control patients. X‐ray diffraction analysis of a cholesterol‐enriched AD sample demonstrated a virtual restoration of the normal membrane bilayer width and electron density profile, suggesting that the cholesterol deficit played a major role in the AD lipid membrane structure perturbation. Addition of β‐amyloid peptide to bovine brain phospholipid membranes signficantly changed the electron density associated with the hydrocarbon core. Alterations in the composition and structure of the membrane bilayer may play an important role in the pathophysiology of AD by altering the activity and catabolism of membrane‐bound proteins, including the β‐amylo

ISSN:0077-8923    

DOI:10.1111/j.1749-6632.1993.tb23027.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY