Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer's disease

Rylett, R. Jane; Ball, Melvyn J.; Colhoun, E. H.

doi:10.1016/0006-8993(83)90017-3

Cited by 179 publications

(57 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This hypothesis is further supported by reduced choline uptake (Rylett et al, 1983) and acetylcholine (ACh) release (Nilsson et al, 1986). Also, decreased levels of ACh are present in the cerebrospinal fluid of AD and vascular dementia patients, and this decrease positively correlates to the degree of severity of dementia (Tohgi et al, 1996).…”

Section: Introductionmentioning

confidence: 93%

Cholinesterase Inhibitor Blockade and its Prevention by Statins of Sympathetic α7-nAChR-Mediated Cerebral Nitrergic Neurogenic Vasodilation

Mozayan

Chen

et al. 2006

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Cholinesterase inhibitors (ChEIs) have been used to treat Alzheimer's disease (AD). The efficacy of these drugs, however, is less than satisfactory. The possibility that ChEIs may have effects unrelated to ChE activity, such as negatively modulate neuronal nicotinic acetylcholine receptors (nAChRs) was evaluated. Since a7-nAChRs on cerebral perivascular sympathetic neurons mediate cerebral parasympathetic-nitrergic vasodilation, effects of physostigmine, neostigmine, and galantamine on a7-nAChR-mediated dilation in isolated porcine basilar arterial rings denuded of endothelium was examined using in vitro tissue bath technique. The results indicated that these ChEIs blocked vasodilation induced by choline (0.3 mmol/L), nicotine (0.1 mmol/L), and transmural nerve stimulation (TNS). The ChEI inhibition of dilation induced by TNS but not by choline or nicotine was prevented by atropine (0.1 lmol/L) pretreatment. Furthermore, using confocal microscopy, significant calcium influx induced by choline and nicotine in cultured porcine superior cervical ganglion (SCG) cells was attenuated by ChEIs. In a7-nAChR-expressed Xenopus oocytes, nicotine-induced inward currents were attenuated by a-bungarotoxin and ChEIs. Moreover, ChEI inhibition of nicotine-and choline-induced dilation was prevented by pretreatment with mevastatin and lovastatin (10 lmol/L), which did not affect ChEI inhibition of TNS-induced relaxation. These findings suggest that ChEIs inhibit the a7-nAChRs located on postganglionic sympathetic nerve terminals of SCG origin, causing a decreased release of nitric oxide in the neighboring nitrergic nerves and cerebral vasodilation. Inhibition of a7-nAChRs leading to a potential cerebral hypoperfusion may contribute to the limitation of ChEIs and question the validity of using a ChEI alone in treating AD. The efficacy of ChEIs may be improved by concurrent use of statins.

show abstract

Section: Introductionmentioning

confidence: 93%

Cholinesterase Inhibitor Blockade and its Prevention by Statins of Sympathetic α7-nAChR-Mediated Cerebral Nitrergic Neurogenic Vasodilation

Mozayan

Chen

et al. 2006

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…Accompanying the loss of neurons in AD pathology, choline acetyltransferase activity (ChAT), high-affinity choline uptake (HACU), acetylcholinesterase (AChE) activity, and the level of acetylcholine (ACh) are reported to be significantly decreased in the hippocampal and cortical regions of the brain (Rylett et al, 1983;Price, 1986;Wurtman, 1992;Quirion, 1993;Geula and Mesulam, 1994). It is suggested that loss of cholinergic neurons contributes to the progressive cognitive deficits observed in AD patients (Bartus et al, 1982;Hohmann et al, 1988;Geula and Mesulam, 1994).…”

Section: Introductionmentioning

confidence: 99%

Amyloid β‐Peptide Inhibits High‐Affinity Choline Uptake and Acetylcholine Release in Rat Hippocampal Slices

Kar

Issa

Seto

et al. 1998

Journal of Neurochemistry

150

View full text Add to dashboard Cite

Abstract:The characteristic pathological features of the postmortem brain of Alzheimer's disease (AD) patients include, among other features, the presence of neuritic plaques composed of amyloid /3-peptide (A~3)and the loss of basal forebrain cholinergic neurons, which innervate the hippocampus and the cortex. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that A/3 accumulation in vivo may initiate and/or contribute to the process of neurodegeneration and thereby the development of AD. However, the mechanisms by which Aj3 peptide influences/causes degeneration of the basal forebrain cholinergic neurons and/or the cognitive impairment characteristic of AD remain obscure. Using in vitro slice preparations, we have recently reported that A/3-related peptides, under acute conditions, potently inhibit K~-evokedendogenous acetyicholine (ACh) release from hippocampus and cortex but not from striatum. In the present study, we have further characterized A/3-mediated inhibition of ACh release and also measured the effects of these peptides on choline acetyltransferase (ChAT) activity and high-affinity choline uptake (HACU) in hippocampal, cortical, and striatal regions of the rat brain. A/3 1_40(10 8M) potently inhibited veratridine-evoked endogenous ACh release from rat hippocampal slices and also decreased the K~-evokedrelease potentiated by the nitric oxidegenerating agent, sodium nitroprusside (SNP). It is interesting that the endogenous cyclic GMP level induced by SNP was found to be unaltered in the presence of 1AT

show abstract

“…The uptake step is particularly important in that it is both rate-limiting and subject to regulation by neuronal impulse activity (14)(15)(16). However, this step has not generally been evaluated in studies with human tissues because fresh material is required to isolate viable nerve terminal particles (synaptosomes) that will maintain their uptake characteristics; the up-regulation of choline uptake associated with neural stimulation decays particularly rapidly postmortem (17,18 (19,20).…”

mentioning

confidence: 99%

Regulatory changes in presynaptic cholinergic function assessed in rapid autopsy material from patients with Alzheimer disease: implications for etiology and therapy.

Slotkin

Seidler

Crain

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Brain regions from patients with or without Alzheimer disease (AD) were obtained within 2 hr of death and examined for indices of presynaptic cholinergic function. Consistent with loss of cholinergic projections, cerebral cortical areas involved in AD exhibited decreased choline acetyltransferase (acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6) activity. However, remaining nerve terminals in these regions displayed marked up-regulation of synaptosomal high affinity [3Hlcholine uptake, a result indicative of relative cholinergic hyperactivity. As choline uptake is also rate-limiting in acetylcholine biosynthesis, these rmdings have implications for both therapy and identification of causes contributing to neuronal death in AD.Alzheimer disease (AD), the leading cause of dementia and currently the fourth leading cause of death in the United States (1), is characterized by the abnormal presence of senile plaques and neurofibrillary tangles in the central nervous system. Neurochemically, the loss of cholinergic projections to the cerebral cortex is the hallmark characteristic ofAD and has served as a focus for studies of its etiology and therapy (2-9). Dietary supplementation with neurotransmitter precursors represents a useful approach to the management of neurodegenerative diseases. The most prominent example is Parkinson disease, in which many ofthe symptoms ofdopaminergic deficiency can be offset with L-dopa (10). In contrast, choline supplementation has proven to be only marginally successful in treating AD (2-9), suggesting either that cholinergic presynaptic function may be affected over and above the loss of terminals or, alternatively, that the clinical dementia is not due solely to cholinergic dysfunction (11-13).Acetylcholine synthesis proceeds via the active, highaffinity uptake of choline by the nerve terminal and subsequent conversion to acetylcholine by the enzyme choline acetyltransferase (ChAT; acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6). The uptake step is particularly important in that it is both rate-limiting and subject to regulation by neuronal impulse activity (14-16). However, this step has not generally been evaluated in studies with human tissues because fresh material is required to isolate viable nerve terminal particles (synaptosomes) that will maintain their uptake characteristics; the up-regulation of choline uptake associated with neural stimulation decays particularly rapidly postmortem (17, 18). The current study measures ChAT activity and synaptosomal [3H]choline uptake obtained from brain regions of AD and non-AD patients less than 2 hr after death. Because choline uptake, but not ChAT, is responsive to nerve stimulation, we have also assessed the uptake/ ChAT ratio as an index of activity corrected for the relative loss of nerve terminals caused by AD. EXPERIMENTAL PROCEDURESPatient Selection and Diagnostic Criteria. Thirty-one patients from the Rapid Autopsy Program were included in this study: 22 with AD (one with coexisting Parkinson disease and one with co...

show abstract

Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer's disease

Cited by 179 publications

References 39 publications

Cholinesterase Inhibitor Blockade and its Prevention by Statins of Sympathetic α7-nAChR-Mediated Cerebral Nitrergic Neurogenic Vasodilation

Cholinesterase Inhibitor Blockade and its Prevention by Statins of Sympathetic α7-nAChR-Mediated Cerebral Nitrergic Neurogenic Vasodilation

Amyloid β‐Peptide Inhibits High‐Affinity Choline Uptake and Acetylcholine Release in Rat Hippocampal Slices

Regulatory changes in presynaptic cholinergic function assessed in rapid autopsy material from patients with Alzheimer disease: implications for etiology and therapy.

Contact Info

Product

Resources

About