Biomedical subjects

A Salehi

Publications and source records attributed to A Salehi.

53 records · Page 3Linked to original sources

PubMed1995

Decreased protein synthetic activity of the hypothalamic tuberomamillary nucleus in Alzheimer's disease as suggested by smaller Golgi apparatus.

The nucleus tuberalis lateralis (NTL) and tuberomamillary nucleus (TM), which are located close together in the tuberal region of the human hypothalamus, are differentially affected by Alzheimer's disease (AD), In the AD, the NTL shows only early cytoskeletal alterations, i.e. pre-tangle stages, while the TM is characterised by advanced Alzheimer's changes, e.g. neurofibrillary degeneration, senile plaques and amyloid deposition. Earlier we showed that the early cytoskeletal alterations in the NTL are not accompanied by changes in protein synthetic activity. The present study was carried out in order to measure the protein synthetic activity of the neighbouring area, the TM, which is severely affected by advanced Alzheimer changes. A polyclonal antibody against MG-160, a conserved membrane sialoglycoprotein of the Golgi apparatus, was used to stain this organelle and using an image analysis system, the size of the Golgi apparatus was measured as an index for synthetic and secretory activity in 15 Alzheimer patients and 21 controls. A significant decrease in the size of the Golgi apparatus was found in the TM neurons in AD, although the cell profile area remained unchanged. These data suggest that the protein synthetic and secretory activity of TM neurons is indeed decreased in AD.

Aged↗

PubMed1995

Early cytoskeletal changes as shown by Alz-50 are not accompanied by decreased neuronal activity.

The nucleus tuberalis lateralis (NTL) is located in the basolateral part of the hypothalamus and is only present as a well-delineated nucleus in human and higher primates. In Alzheimer's disease (AD), NTL neurons show strong early cytoskeletal alterations, as revealed by the antibody Alz-50, but practically no senile plaques or neurofibrillary tangles. To study whether the activity of NTL neurons decreases when cytoskeletal changes appear, i.e., during aging and in AD, we applied a polyclonal antibody raised against the medial cisternae of the Golgi apparatus (GA). The size of the GA and the cell profile of NTL neurons, two established parameters for neuronal activity, were measured by an image analysis system. No significant change in the size of the profiles of the GA or of the neurons was observed in this nucleus during aging or AD. Earlier studies have shown that there is no decrease in cell number in the NTL in AD. We conclude that in the NTL an early hallmark of AD, i.e., cytoskeletal changes as stained by Alz-50, does not correlate with decreased neuronal activity, as reflected by the size of the GA, nor with a decrease in cell number. In addition, we found that the very early occurring and abundant presence of lipofuscin in NTL neurons does not go together with decreased neuronal activity.

Adult↗

PubMed1995

Decreased activity of hippocampal neurons in Alzheimer's disease is not related to the presence of neurofibrillary tangles.

Numerous studies have established the key role of the Golgi apparatus (GA) in post-translational processing, transport and targeting of proteins destined for secretion, lysosomes and plasma membranes. Moreover, several studies performed in our laboratories have shown that the size of the immunocytochemically detected neuronal GA is a reliable index of neuronal activity in aging, Alzheimer's disease (AD) and amyotrophic lateral sclerosis. It has been suggested that in AD there is decreased neuronal activity, e.g. in terms of glucose metabolism and protein synthetic capability. To further explore the hypothesis of decreased neuronal activity in AD, in this study the size of the GA was measured in pyramidal neurons of the CA1 area of the hippocampus of non-demented controls and AD patients. The size of the GA was measured separately in neurons with and without neurofibrillary tangles (NFT). Moreover, in order to establish a correlation between the density of NFT and the size of the GA, the density of extraneuronal NFT was determined around each neuron and related to the size of its GA. The results, quantified by image analysis, indicate that there is a significant reduction in GA size in the neurons of the CA1 area of the hippocampus of AD patients. However, there was no significant relationship between the size of the GA and the presence or absence of intracellular NFT. In addition, there was no correlation between the density of extracellular NFT and GA size of adjacent neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1995

The pseudotetrasaccharide acarbose inhibits pancreatic islet glucan-1,4-alpha-glucosidase activity in parallel with a suppressive action on glucose-induced insulin release.

The pseudotetrasaccharide acarbose, previously known as a potent inhibitor of intestinal alpha-glucoside hydrolases, was investigated with regard to its influence on islet lysosomal enzyme activities and the insulin secretory processes. We observed that acarbose was a potent inhibitor of mouse islet lysosomal acid glucan-1,4-alpha-glucosidase activity, EC50 approximately 5 mumol/l, as well as of acid alpha-glucosidase activity. In contrast, acarbose did not influence other lysosomal enzyme activities such as acid phosphatase and N-acetyl-beta-D-glucosaminidase. Neutral alpha-glucosidase (endoplasmic reticulum) was only moderately inhibited in homogenate and was unaffected in intact islets. Incubation of isolated mouse islets with acarbose revealed that the pseudotetrasaccharide was a strong inhibitor of glucose-induced insulin secretion, EC50 approximately 500 nmol/l, and a significant inhibition was already observed at a concentration of acarbose as low as 100 nmol/l. The acarbose analogue maltotetrose did not influence either glucose-induced insulin release or islet lysosomal enzyme activities. Further, acarbose as well as two other alpha-glucoside hydrolase inhibitors, the deoxynojirimycin derivatives miglitol and emiglitate, did not affect islet glucose oxidation at low or high glucose levels. Acarbose also inhibited insulin release induced by the sulfonylurea glibenclamide, whereas insulin secretion stimulated by the cholinergic muscarinic agonist carbachol or the phosphodiesterase inhibitor isobutylmethylxanthine was unaffected by the drug. Moreover, complementary in vivo experiments showed that pretreatment of mice with acarbose to allow for endocytosis of the compound markedly suppressed the insulin secretory response to an intravenous glucose load.(ABSTRACT TRUNCATED AT 250 WORDS)

Acarbose↗

PubMed1994

Decreased neuronal activity in the nucleus basalis of Meynert in Alzheimer's disease as suggested by the size of the Golgi apparatus.

In order to study changes in neuronal activity in the nucleus basalis of Meynert in aging and Alzheimer's disease, we applied a polyclonal antibody directed against the Golgi apparatus on formalin-fixed, paraffin-embedded material. Subsequently, an image analysis system was used to measure the size of the Golgi apparatus in (i) all nucleus basalis neurons and also separately in (ii) the remaining large cells (perikaryonal diameter > 30 microns). A significant reduction of 49% in the size of the Golgi apparatus was found in the entire population of nucleus basalis neurons in Alzheimer's disease. Furthermore, although there was no significant decrease in the size of the persisting large neurons in the nucleus basalis of Meynert, a significantly decreased size of the Golgi apparatus was found in these neurons in Alzheimer's disease. These results suggest that the overall activity of nucleus basalis neurons is severely decreased in Alzheimer's disease. Furthermore, these data support the idea that atrophy and decreased activity are the main phenomena in the nucleus basalis in Alzheimer's disease; they also indicate that the size of the Golgi apparatus is a sensitive parameter to follow this process.

Adult↗

PubMed1994

Activation of vasopressin neurons in aging and Alzheimer's disease.

The supraoptic (SON) and paraventricular nuclei (PVN) of the human hypothalamus are production sites of vasopressin (AVP) and oxytocin (OXT). Although the hypothalamus is affected in Alzheimer's disease (AD), previous work has not only shown that in these two nuclei no neurons are lost, neither during aging nor in AD, but that the number of AVP-expressing neurons and their nucleolar size had even increased with age. These observations indicated that the peptide synthesis of the AVP neurons was activated in the oldest age-groups. Recently published, qualitative observations, using the area of the Golgi Apparatus (GA) as a sensitive parameter for neurosecretory activity, confirmed the activation of SON and PVN neurons with age in human; however, in this report the neurons were not identified according to their neuropeptide content. In the present quantitative study we determined whether the AVP neurons were indeed activated as a result of the aging process in controls and AD patients. We applied a polyclonal antiserum directed against the medial cisternae of the GA on formalin-fixed, paraffin-embedded tissue sections taken from the dorsolateral SON (dl-SON) of 10 controls and 10 AD patients, and performed our measurements in this area that is known to be predominantly occupied (90-95%) by AVP neurons. In addition, the sparse OXT cells present in the area of study, were excluded from the measurements on the basis of alternative sections stained for OXT. In the dl-SON, the area occupied by the GA and the cellular profile area per patient were quaNtified by means of image analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Changes in islet glucan-1,4-alpha-glucosidase activity modulate sulphonylurea-induced but not cholinergic insulin secretion.

We have previously presented indirect in vivo evidence for the involvement of islet acid glucan-1,4-alpha-glucosidase (acid amyloglucosidase), a lysosomal glucose-producing enzyme, in certain insulin secretory processes. In the present in vitro and in vivo investigation, we studied whether differential changes in islet acid amyloglucosidase activity would be related to the insulin secretory response induced by two mechanistically different secretagogues, the sulphonylurea derivative, glibenclamide and the acetylcholine receptor agonist, carbachol. It was observed that the selective alpha-glucosidehydrolase inhibitors emiglitate and acarbose markedly reduced glibenclamide-induced insulin release from isolated islets. Insulin release stimulated by carbachol or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate), was not inhibited. Basal insulin secretion was unaffected by emiglitate and acarbose. Further, pretreatment of mice with emiglitate resulted in a marked reduction of the in vivo insulin response to glibenclamide. Moreover, in vivo pretreatment with purified fungal amyloglucosidase ('enzyme replacement'), a procedure known to increase islet amyloglucosidase activity, greatly enhanced the insulin response to i.v. glibenclamide. This insulin release was accompanied by a marked depression of the blood glucose levels. In contrast, enzyme pretreatment did not influence the insulin response or the blood glucose levels after carbachol. The data strongly suggest that islet acid amyloglucosidase is involved in the insulin secretory processes induced by glibenclamide but not in those involving stimulation of muscarinic receptors or direct activation of protein kinase C. The results also indicate separate or at least partially separate pathways for insulin release induced by glibenclamide and cholinergic stimulation.

1-Deoxynojirimycin↗

PubMed1993

Ca2+ deficiency, selective alpha-glucosidehydrolase inhibition, and insulin secretion.

We investigated the relation between activities of islet glycogenolytic alpha-glucosidehydrolases and insulin secretion induced by glucose and 3-isobutyl-1-methylxanthine (IBMX) by means of suppressing 1) insulin release (Ca2+ deficiency) and 2) islet alpha-glucosidehydrolase activity (selective inhibition by the deoxynojirimycin derivative miglitol). Additionally, the in vivo insulin response to both secretagogues was examined. We observed that, similar to glucose-induced insulin release, islet glycogenolytic hydrolases (acid amyloglucosidase, acid alpha-glucosidase) were highly Ca2+ dependent. Acid phosphatase, N-acetyl-beta-D-glucosaminidase, or neutral alpha-glucosidase (endoplasmic reticulum) was not influenced by Ca2+ deficiency. In Ca2+ deficiency IBMX-induced insulin release was unaffected and was accompanied by reduced activities of islet alpha-glucosidehydrolases. Miglitol strongly inhibited glucose-induced insulin release concomitant with a marked suppression of islet alpha-glucosidehydrolase activities. Direct addition of miglitol to islet homogenates suppressed acid amyloglucosidase [half-maximal effective concentration (EC50) approximately 10(-6) M] and acid alpha-glucosidase. Acid phosphatase and N-acetyl-beta-D-glucosaminidase were unaffected. The miglitol-induced inhibition of glucose-stimulated insulin release was dose dependent (EC50 approximately 10(-6) M) and displayed a remarkable parallelism with the inhibition curve for acid amyloglucosidase. The in vivo insulin secretory response to glucose was markedly reduced in dystrophic mice (low amyloglucosidase), whereas the response to IBMX was unaffected. In summary, islet glycogenolytic hydrolases are Ca2+ dependent, and acid amyloglucosidase is directly involved in the multifactorial process of glucose-induced insulin release. In contrast the mechanisms of IBMX-stimulated insulin secretion operate independently of these enzymes. The effects of miglitol, a drug currently used in diabetes therapy, deserves further investigation.

1-Deoxynojirimycin↗

PubMed1993

Islet glucan-1,4-alpha-glucosidase: differential influence on insulin secretion induced by glucose and isobutylmethylxanthine in mice.

In previous in-vivo studies we have presented indirect evidence for the involvement of islet acid glucan-1,4-alpha-glucosidase (acid amyloglucosidase), a lysosomal glycogen-hydrolysing enzyme, in certain insulin secretory processes. In the present combined in-vitro and in-vivo investigation, we studied whether differential changes in islet acid amyloglucosidase activity were related to the insulin secretory response induced by two mechanistically different secretagogues, glucose and isobutylmethylxanthine (IBMX). It was observed that addition of the selective alpha-glucosidehydrolase inhibitor emiglitate (1 mmol/l) to isolated pancreatic islets resulted in a marked reduction of glucose-induced insulin release. This was accompanied by a pronounced suppression of islet activities of acid amyloglucosidase and acid alpha-glucosidase, whereas other lysosomal enzyme activities, such as acid phosphatase and N-acetyl-beta-D-glucosaminidase, were unaffected. Furthermore, islets first incubated with emiglitate in the presence of high (16.7 mmol/l) glucose released less insulin than untreated controls in response to glucose in a second incubation period in the absence of emiglitate. In contrast, IBMX-induced insulin release was not influenced by emiglitate although accompanied by a marked reduction of islet activities of all three alpha-glucosidehydrolases. Basal insulin secretion (1 mmol glucose/l) was unaffected in the presence of emiglitate. In-vivo pretreatment of mice with highly purified fungal amyloglucosidase ('enzyme replacement'), a procedure known to increase islet amyloglucosidase activity, resulted in a greatly enhanced insulin secretory response to an i.v. glucose load. The increase in insulin release was accompanied by a markedly improved glucose tolerance curve in these animals. In contrast, enzyme pretreatment did not influence the insulin response or the blood glucose levels after an i.v. injection of IBMX. The data lend further support to our hypothesis that islet acid amyloglucosidase is involved in the multifactorial insulin secretory processes induced by glucose but not in those involving direct activation of the cyclic AMP system. The results also indicate separate, or at least partially separate, pathways for insulin release induced by glucose and IBMX.

1-Deoxynojirimycin↗

PubMed1988