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Journal ArticleDOI

Reduction of acetylcholine in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice

11 Nov 2021-Scientific Reports (Springer Science and Business Media LLC)-Vol. 11, Iss: 1, pp 22072
TL;DR: In this article, the authors confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method, suggesting that Ach may be a cholinergic regulator in the septo-hippocampal network.
Abstract: The cholinergic efferent network from the medial septal nucleus to the hippocampus plays an important role in learning and memory processes. This cholinergic projection can generate theta oscillations in the hippocampus to encode novel information. Hippocampal cholinergic neurostimulating peptide (HCNP), which induces acetylcholine (Ach) synthesis in the medial septal nuclei of an explant culture system, was purified from the soluble fraction of postnatal rat hippocampus. HCNP is processed from the N-terminal region of a 186-amino acid, 21-kDa HCNP precursor protein, also known as Raf kinase inhibitory protein and phosphatidylethanolamine-binding protein 1. Here, we confirmed direct reduction of Ach release in the hippocampus of freely moving HCNP-pp knockout mice under an arousal state by the microdialysis method. The levels of vesicular acetylcholine transporter were also decreased in the hippocampus of these mice in comparison with those in control mice, suggesting there was decreased incorporation of Ach into the synaptic vesicle. These results potently indicate that HCNP may be a cholinergic regulator in the septo-hippocampal network.
Citations
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Journal ArticleDOI
TL;DR: In this paper , the importance of hippocampal cholinergic neuro-stimulating peptide (HCNP) in inducing acetylcholine synthesis in the medial septal nucleus was investigated.
Abstract: Abstract Cholinergic activation can enhance glutamatergic activity in the hippocampus under pathologic conditions, such as Alzheimer’s disease. The aim of the present study was to elucidate the relationship between glutamatergic neural functional decline and cholinergic neural dysfunction in the hippocampus. We report the importance of hippocampal cholinergic neurostimulating peptide (HCNP) in inducing acetylcholine synthesis in the medial septal nucleus. Here, we demonstrate that HCNP-precursor protein (pp) knockout (KO) mice electrophysiologically presented with glutamatergic dysfunction in the hippocampus with age. The impairment of cholinergic function via a decrease in vesicular acetylcholine transporter in the pre-synapse with reactive upregulation of the muscarinic M1 receptor may be partly involved in glutamatergic dysfunction in the hippocampus of HCNP-pp KO mice. The results, in combination with our previous reports that show the reduction of hippocampal theta power through a decrease of a region-specific choline acetyltransferase in the stratum oriens of CA1 and the decrease of acetylcholine concentration in the hippocampus, may indicate the defined cholinergic dysfunction in HCNP-pp KO mice. This may also support that HCNP-pp KO mice are appropriate genetic models for cholinergic functional impairment in septo-hippocampal interactions. Therefore, according to the cholinergic hypothesis, the model mice might are potential partial pathological animal models for Alzheimer’s disease.

1 citations

Posted ContentDOI
29 Sep 2022
TL;DR: In this paper , it was shown that HCNP-precursor protein (pp) knockout mice electrophysiologically presented with glutamatergic dysfunction in the hippocampus with age.
Abstract: Abstract Cholinergic activation can enhance glutamatergic activity in the hippocampus under pathologic conditions, such as Alzheimer’s disease and Lewy body disease. We aimed to elucidate the relationship between glutamatergic neural suppression and cholinergic neural dysfunction. We reported the importance of hippocampal cholinergic neurostimulating peptide (HCNP) in inducing acetylcholine synthesis in the MSN. Here, we demonstrated that HCNP-precursor protein (pp) knockout (KO) mice electrophysiologically presented with glutamatergic dysfunction in the hippocampus with age. The impairment of cholinergic dysfunction and the vesicular acetylcholine transporter decrease in the pre-synapse with reactive upregulation of the muscarinic M1 receptor may be partly involved in glutamatergic dysfunction in the hippocampus of HCNP-pp KO mice. These results in combination with our previous reports support the reduction of hippocampal theta power as region-specific in the stratum oriens of CA1 and a decrease in choline acetyltransferase and a direct reduction in acetylcholine in the hippocampus. This may support that HCNP-pp KO mice are an adequate genetic model for cholinergic functional impairment in septo-hippocampal interactions. Thus, according to cholinergic hypothesis this model mice might have a potential as a partial pathological animal model for Alzheimer’s disease.
Journal ArticleDOI
TL;DR: In this article , the authors investigated whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholineergic dysfunction of HCNP-pp conditional knockout (cKO).
Abstract: The cholinergic efferent network from the medial septal nucleus to the hippocampus is crucial for learning and memory. This study aimed to clarify whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholinergic dysfunction of HCNP precursor protein (HCNP-pp) conditional knockout (cKO). Chemically synthesized HCNP or a vehicle were continuously administered into the cerebral ventricle of HCNP-pp cKO mice and littermate floxed (control) mice for two weeks via osmotic pumps. We immunohistochemically measured the cholinergic axon volume in the stratum oriens and functionally evaluated the local field potential in the CA1. Furthermore, choline acetyltransferase (ChAT) and nerve growth factor (NGF) receptor (TrkA and p75NTR) abundances were quantified in wild-type (WT) mice administered HCNP or the vehicle. As a result, HCNP administration morphologically increased the cholinergic axonal volume and electrophysiological theta power in HCNP-pp cKO and control mice. Following the administration of HCNP to WT mice, TrkA and p75NTR levels also decreased significantly. These data suggest that extrinsic HCNP may compensate for the reduced cholinergic axonal volume and theta power in HCNP-pp cKO mice. HCNP may function complementarily to NGF in the cholinergic network in vivo. HCNP may represent a therapeutic candidate for neurological diseases with cholinergic dysfunction, e.g., Alzheimer’s disease and Lewy body dementia.
References
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Journal ArticleDOI
TL;DR: It appears that the age-related changes of memory function as well as some of the behavioral disturbances seen in the dementia of Alzheimer's Disease may be related to pathological alterations along central cholinergic pathways.

2,280 citations

Journal ArticleDOI
TL;DR: Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events and significantly benefits the cognitive, functional, and behavioral symptoms of AD.
Abstract: Objective: To investigate the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. Methods: A 5-month multicenter, placebo-controlled, double-blind trial. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24 mg/day. Outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog), the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory. Standard safety evaluations and adverse event monitoring were carried out. Results: After 5 months, the galantamine–placebo differences on ADAS-cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group ( p Conclusions: Galantamine 16 and 24 mg/day significantly benefits the cognitive, functional, and behavioral symptoms of AD as compared with placebo. Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events.

898 citations

Journal ArticleDOI
09 Sep 1999-Nature
TL;DR: RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK module and competitively disrupts the interaction between these kinases.
Abstract: Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK module.

833 citations

Journal ArticleDOI
Raymond T. Bartus1
TL;DR: A review of the current status of the cholinergic hypothesis in the context of continuing efforts to improve upon existing treatments for Alzheimer's disease and explores the role that animal models might continue to play as discussed by the authors.

763 citations

Journal ArticleDOI
TL;DR: The use ofdonepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo, and there was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 was obtained at a concentration of 15.6 ng/mL.
Abstract: Methods: This was a 12-week, double-blind, placebocontrolled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS-cog) and Clinician’s Interview˛Based Impression of Change including caregiver information (CIBIC plus). Results: A total of 468 patients entered the study, more than 97% of whom were included in the intention-totreat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P,.001); 0.3 and 0.4 units for CIBIC plus (P#.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P#.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (± SEM) donepezil plasma concentrations at study end point were 25.9 ± 0.7 ng/mL and 50.6 ± 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (± SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% ± 0.9% and 74.7% ± 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P,.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAScog (P,.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%˛78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatmentemergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. Conclusion: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease. Arch Intern Med. 1998;158:1021-1031

744 citations