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A Salehi

Publications and source records attributed to A Salehi.

At least 19 recordsLinked to original sources
PubMed2000

P75 neurotrophin receptor in the nucleus basalis of meynert in relation to age, sex, and Alzheimer's disease.

In a previous study we showed that the staining of tyrosine kinase receptors (trks), which are high-affinity neurotrophin receptors (NTRs), is strongly diminished in the nucleus basalis of Meynert (NBM) of Alzheimer's disease (AD) patients, which may explain the lack of effect of NGF therapy in AD patients so far. Since the literature regarding the expression of low-affinity NTRs was rather controversial, the aim of the present study was to examine (i) possible changes in the staining of low-affinity NTRs, i.e., p75 in the human NBM, an area that is severely affected in AD; and (ii) alterations of these receptors in relation to risk factors for AD, e. g., age, sex, and menopause. Brain material of 31 controls and 30 AD patients was obtained at autopsy, embedded in paraffin, and stained immunocytochemically. Using an image analysis system, we quantified p75 immunoreactivity in both cell bodies and fibers at the level of the NBM. Our results showed a significant diminishment of p75 immunoreactivity in both cell bodies and fibers of NBM neurons in AD. We did not find any relationship between age or sex and the expression of p75 receptor in cell bodies. However, there was a clearly positive relationship between age and fiber staining in AD patients which suggests the occurrence of a p75 transport disorder as an early event in the process of AD. These observations and the earlier reported decreased staining of trk receptors show that degeneration of NBM neurons in AD is associated with a decreased neurotrophin responsiveness of NBM neurons in AD and that therapeutic strategies should be directed toward upregulation of receptors or facilitation of transport before an effect of neurotrophins in AD may be expected.

Age Factors↗
PubMed2000

Sex- and age-related P75 neurotrophin receptor expression in the human supraoptic nucleus.

The human supraoptic nucleus (SON) is the main production site of plasma vasopressin. Previously, using the Golgi apparatus and cell size as measures for neuronal metabolic activity, an activation of vasopressinergic neurons was found during ageing in the human SON in women but not in men. We hypothesized that the low-affinity neurotrophin receptor p75 (p75(NTR)) might be involved in the mechanism of activation of vasopressin neurons in postmenopausal women, since this receptor was found to be expressed in the SON neurons of aged individuals, and because p75(NTR) expression was shown to be suppressed by estrogens. Therefore, we investigated whether p75(NTR) immunoreactivity in the SON neurons was age- and sex-dependent. For this purpose, we studied paraffin sections of the SON in 32 postmortem brains of control patients ranging in age from 29 to 94 years with an anti-p75(NTR) antibody and determined the area of p75(NTR) immunoreactivity per neuron using an image analysis system. To study whether the p75(NTR) might also participate in the activation of SON neurons, we related Golgi apparatus size to the area of p75(NTR) immunoreactivity per cell in the same patients. We found that the area of p75(NTR) immunoreactivity per cell correlated indeed significantly with age and with Golgi apparatus size only in women but not in men. Therefore, our results suggest that p75(NTR) is involved in postmenopausal activation of vasopressinergic neurons in the human SON.

Adult↗
PubMed2000

Nitric oxide, islet acid glucan-1,4-alpha-glucosidase activity and nutrient-stimulated insulin secretion.

The mechanism of nutrient-evoked insulin release is clearly complex. One part of that mechanism is postulated to be the activation of the glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. As nitric oxide (NO) has been found to be a potent inhibitor of glucose-stimulated insulin secretion, we have now investigated a possible influence of exogenous NO and inhibition of endogenous NO production on islet acid glucan-1,4-alpha-glucosidase activity in relation to insulin release stimulated by glucose and l-arginine. In isolated islets, NO derived from the intracellular NO donor hydroxylamine inhibited the activation of acid glucan-1, 4-alpha-glucosidase and its isoform acid alpha-glucosidase in parallel with inhibition of glucose-stimulated insulin release. In comparison, other lysosomal enzymes were largely unaffected. Similarly, the spontaneous NO donor sodium nitroprusside, as well as NO gas, when added to islet homogenates, suppressed the activities of these acid alpha-glucosidehydrolases and, to a lesser extent, the activities of other lysosomal enzymes. Finally, in the presence of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester, insulin release from isolated islets stimulated by glucose or l-arginine was markedly potentiated in parallel with an accompanying increase in the activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase. Other lysosomal enzymes and neutral alpha-glucosidase were not influenced. We propose that an important inhibitory effect of NO on the insulin secretory processes stimulated by glucose and l-arginine is exerted via inactivation of islet acid glucan-1,4-alpha-glucosidase, a putative key enzyme in nutrient-stimulated insulin release.

Animals↗
PubMed1999

Gastrectomy induces impaired insulin and glucagon secretion: evidence for a gastro-insular axis in mice.

1. Mice were subjected to gastrectomy (GX) or food deprivation (24 h). The release of insulin and glucagon in response to different secretagogues was monitored in vivo and in isolated islets 3-4 weeks after surgery. 2. GX animals responded to glucose with an impaired glucose tolerance and a poor increase in plasma insulin. Islets from GX or food-deprived mice displayed impaired insulin release to high glucose and enhanced glucagon release at low glucose. 3. After GX the insulinogenic index, Delta insulin (microU ml-1)/Delta glucose (mg ml-1), was suppressed by 65% after oral glucose and by 59% after i.v. glucose. The integrated insulin response after oral glucose was reduced by 90% in GX mice. After i.v. glucose the reduction was 67%. 4. Carbachol-induced insulin release in vivo was reduced after food deprivation and exaggerated after GX. Carbachol-stimulated glucagon secretion was suppressed after GX and after food deprivation. A similar pattern was found in vitro. 5. Cyclic AMP activation (by the phosphodiesterase inhibitor isobutylmethylxanthine or the adenylate cyclase stimulator forskolin) induced a greater insulin response in GX or food-deprived mice than in sham-operated, fed mice. A similar pattern was found in vitro. The glucagon response was enhanced in vitro but not in vivo. 6. Crude extracts of rat oxyntic mucosa enhanced basal as well as glucose-induced insulin release from isolated islets, whereas glucagon release was markedly inhibited. The effects were dose dependent, the inhibition of glucagon release being achieved at lower concentrations than the potentiation of glucose-induced insulin release. The active principle was inactivated by incubation with trypsin or leucine aminopeptidase. 7. The data suggest that a circulating agent, probably a peptide, from gastric oxyntic mucosa stimulates glucose-induced insulin secretion. It also suppresses glucagon secretion. The GX-evoked impairment of the insulin (and glucagon) response to glucose is partly compensated for by an enhanced insulin response to cholinergic and/or cyclic AMP activation.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Diminished neuronal metabolic activity in Alzheimer's disease. Review article.

An increasing number of studies have appeared in the literature suggesting that Alzheimer's disease (AD) is a hypometabolic brain disorder. Decreased metabolism in AD has been revealed by a variety of in vivo and postmortem methods and techniques including positron emission tomography and glucose metabolism. We used the size of the Golgi apparatus (GA) and cell profile area as indicators of neuronal activity in postmortem material. Using an antibody against MG-160, a sialoglycoprotein of the medial cisternae of the GA, we were able to visualize and quantify the GA area. In a series of experiments, we tried to relate neuronal metabolism to different hallmarks of AD, i.e. plaques and tangles, and also to genetic risk factors for AD like age and (apolipoprotein E) ApoE polymorphism. Our results showed that in AD there is indeed a clear reduction in brain metabolism in several severely affected brain regions including the nucleus basalis of Meynert (NBM), the CA1 area of the hippocampus and the hypothalamic tuberomamillary nucleus. However, the reduction in neuronal activity did not seem to be caused by the presence of neuropathological hallmarks of AD, i.e. plaques and tangles. There was, however, a clear relationship between the presence of ApoE epsilon4 alleles and a decrease in GA size. Our data suggest that decreased neuronal activity and neuropathological hallmarks of AD, such as plaques and tangles, are basically independent phenomena. Moreover, ApoE epsilon4 may participate in the pathogenesis of AD by decreasing neuronal metabolism. The main implication of these findings is that therapeutic strategies in AD should be focussed on reactivation of neuronal metabolism.

Age Factors↗
PubMed1999

Activity of vasopressinergic neurones of the human supraoptic nucleus is age- and sex-dependent.

In the human hypothalamus, arginine-vasopressin (AVP) is produced for a major part by the neurones of the supraoptic nucleus (SON). Since plasma AVP levels in men were reported to be higher than those of women and we did not find a sex difference in the neurone number, a higher vasopressinergic neurone activity was supposed to be present in the SON of men. Therefore we studied the size of the Golgi-apparatus (GA), which has been demonstrated previously to be a sensitive parameter for protein synthetic ability of neurones, in 15 men and 17 women ranging in age from 29 to 94 years. A polyclonal antibody against immunoaffinity purified MG-160, a sialoglycoprotein of the medial cisternae of the GA was applied on paraffin-embedded sections containing the dorsolateral SON (dl-SON) from which 90-95% of neurones are vasopressinergic. SON areas that contain oxytocin (OT) cells were excluded on the basis of adjacent sections stained with a monoclonal antibody against OT. By means of an image analysis system the size of the GA and the cellular profile area were determined in dl-SON neurones with a nucleolus. Our results showed indeed an age-dependent sex difference in the size of the GA that appeared to be twice as large in young men (< or = 50 years old) than in young women of the same age. The size of the GA increased with age in women but not in men. In addition, the mean cell profile area, another measure for neuronal activity, was significantly larger in young men than in young women and was in old women larger than in young women. In conclusion, these data show the presence of a sex-dependent age-difference in the activity of vasopressinergic neurones in dl-SON which may relate to differences in AVP and sex hormone levels and kidney AVP receptors.

Adult↗
PubMed1999

Photoelastic analysis of stresses produced by different acetabular cups.

Porous-coated acetabular components can provide long-term biologic fixation to bone. However, the periacetabular stress patterns and mechanisms by which different types of cementless acetabular cups obtain initial stability is not clear. In the current study, periacetabular stresses produced by different cementless acetabular cup geometries were quantitated using a three-dimensional photoelastic model. The cup geometries consisted of trispiked, finned, hemispherical, and nonhemispherical (wider than a hemisphere at the periphery) geometries. The cup models were loaded incrementally in the photoelastic material to simulate periacetabular stress distributions at the time of implantation during surgery rather than under physiologic weightbearing loads. The peripheral stress distributions and their magnitudes induced by the trispiked and oversized hemispherical cups were similar, but the trispiked cup induced localized high stress regions where the spikes penetrate the bone model. The fins separated the periacetabular material into quadrants, which was associated with decreased peripheral stresses. A nonhemispherical geometry with a wider diameter at the rim than a hemisphere increased peripheral stresses more than an oversized hemispherical geometry and required less force to seat the implant. Although various cementless acetabular cups can perform well clinically, they produce different periacetabular stresses and appear to obtain initial fixation by different mechanisms.

Acetabulum↗
PubMed1999

Dysfunction of the islet lysosomal system conveys impairment of glucose-induced insulin release in the diabetic GK rat.

Accumulated evidence links an important signal involved in glucose-stimulated insulin release to the activation of the islet lysosomal glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. We have analyzed the function of the lysosomal system/lysosomal enzyme activities in pancreatic islets of young (6-8 weeks), spontaneously diabetic, GK (Goto-Kakizaki) rats and Wistar control rats in relation to glucose-induced insulin release. The insulin secretory response to glucose was markedly impaired in the GK rat, but was restored by the adenylate cyclase activator forskolin. Islet activities of classical lysosomal enzymes, e.g.. acid phosphatase, N-acetyl-beta-D-glucosaminidase, beta-glucuronidase, and cathepsin D, were reduced by 20-35% in the GK rat compared with those in Wistar controls. In contrast, the activities of the lysosomal alpha-glucosidehydrolases, i.e.. acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase, were increased by 40-50%. Neutral alpha-glucosidase (endoplasmic reticulum) was unaffected. Comparative analysis of liver tissue showed that lysosomal enzyme activities were of the same magnitude in GK and Wistar rats. Notably, in Wistar rats, the activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase were approximately 15-fold higher in islets than in liver. Other lysosomal enzymes did not display such a difference. Normalization of glycemia in GK rats by phlorizin administered for 9 days did not influence either the lysosomal alpha-glucosidehydrolase activities or other lysosomal enzyme activities in GK islets. Finally, the pseudotetrasaccharide acarbose, which accumulates in the lysosomal system, inhibited acid glucan-1,4-alpha-glucosidase activity in parallel with its inhibitory action on glucose-induced insulin release in intact Wistar islets, whereas no effect was recorded for either parameter in intact GK islets. In contrast, acarbose inhibited the enzyme activity equally in islet homogenates from both GK and Wistar rats, showing that the catalytic activity of the enzyme itself in disrupted cells was unaffected. We propose that dysfunction of the islet lysosomal/vacuolar system is an important defect impairing the transduction mechanisms for glucose-induced insulin release in the GK rat.

Acarbose↗
PubMed1999

Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice.

We have studied, by a combined in vitro and in vivo approach, the relation between the inhibitory action of N(G)-nitro-l-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase (NOS), on the activity of islet constitutive NOS (cNOS) and glucose regulation of islet hormone release in mice. The cNOS activity in islets incubated in vitro at 20 mM glucose was not appreciably affected by 0.05 or 0.5 mM L-NAME, but was greatly suppressed (-60%) by 5 mM L-NAME. Similarly, glucose-stimulated insulin release was unaffected by the lower concentrations of L-NAME but greatly enhanced in the presence of 5 mM of the NOS inhibitor. In incubated islets inhibition of cNOS activity resulted in a modestly enhanced insulin release in the absence of glucose, did not display any effect at physiological or subphysiological glucose concentrations, but resulted in a markedly potentiated insulin release at hyperglycaemic glucose concentrations. In the absence of glucose, glucagon secretion was suppressed by L-NAME. The dynamics of glucose-induced insulin release and (45)Ca(2+) efflux from perifused islets revealed that L-NAME caused an immediate potentiation of insulin release, and a slight increase in (45)Ca(2+) efflux. In islets depolarized with 30 mM K(+) in the presence of the K(+)(ATP) channel opener, diazoxide, L-NAME still greatly potentiated glucose-induced insulin release. Finally, an i.v. injection of glucose to mice pretreated with L-NAME was followed by a markedly potentiated insulin response, and an improved glucose tolerance. In accordance, islets isolated directly ex vivo after L-NAME injection displayed a markedly reduced cNOS activity. In conclusion, we have shown here, for the first time, that biochemically verified suppression of islet cNOS activity, induced by the NOS inhibitor L-NAME, is accompanied by a marked potentiation of glucose-stimulated insulin release both in vitro and in vivo. The major action of NO to inhibit glucose-induced insulin release is probably not primarily linked to changes in Ca(2+) fluxes and is exerted mainly independently of membrane depolarization events.

Analysis of Variance↗
PubMed1998

Aggravated decrease in the activity of nucleus basalis neurons in Alzheimer's disease is apolipoprotein E-type dependent.

As reported before, the metabolic activity of nucleus basalis neurons is reduced significantly in Alzheimer patients. Because the apolipoprotein E (ApoE) epsilon4 genotype is a major risk factor for Alzheimer's disease (AD), we determined whether the decrease in metabolic activity in nucleus basalis neurons in AD is ApoE-type dependent. The size of the Golgi apparatus (GA) was determined as a measure of neuronal metabolic activity in 30 controls and 41 AD patients with a known ApoE genotype by using an image analysis system in the nucleus basalis of Meynert. A polyclonal antibody directed against MG-160, a sialoglycoprotein of the GA, was used to visualize this organelle. There was a very strong reduction in the size of the GA in the nucleus basalis of AD patients. Furthermore, a strong and significant extra reduction in the size of the GA was found in the nucleus basalis neurons of AD patients with either one or two ApoE epsilon4 alleles compared with Alzheimer patients without ApoE epsilon4 alleles. Our data show that the decreased activity of nucleus basalis neurons in AD is ApoE epsilon4 dependent and suggest that ApoE epsilon4 participates in the pathogenesis of AD by decreasing neuronal metabolism.

Adult↗
PubMed1998

Increased expression of the TIAR protein in the hippocampus of Alzheimer patients.

T-cell restricted intracellular antigen related protein (TIAR) is an RNA-binding protein that is supposed to be involved in the process of stress-induced apoptosis. TIAR triggers DNA fragmentation in permeabilized thymocytes and its expression diminishes in the cell nucleus and rises simultaneously in the cytoplasm during Fas-induced cell death. Using a monoclonal antibody against TIAR, we stained different areas of the hippocampus from seven controls and 14 patients with Alzheimer's disease (AD). There was a clear expression of TIAR in the hippocampus of non-demented controls. Surprisingly, a significant increase was found in the expression of TIAR in the hippocampal area in AD. The increased expression of TIAR in AD may be related to the process of neurodegeneration in the hippocampus.

Aged↗
PubMed1998

Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients.

The cerebral cortex of Alzheimer's and Down syndrome patients is characterized by the presence of protein deposits in neurofibrillary tangles, neuritic plaques, and neuropil threads. These structures were shown to contain forms of beta amyloid precursor protein and ubiquitin-B that are aberrant (+1 proteins) in the carboxyl terminus. The +1 proteins were not found in young control patients, whereas the presence of ubiquitin-B+1 in elderly control patients may indicate early stages of neurodegeneration. The two species of +1 proteins displayed cellular colocalization, suggesting a common origin, operating at the transcriptional level or by posttranscriptional editing of RNA. This type of transcript mutation is likely an important factor in the widely occurring nonfamilial early- and late-onset forms of Alzheimer's disease.

Aged↗
PubMed1998

Biochemical and ultra-structural reactions to parenteral nutrition with two different fat emulsions in rats.

OBJECTIVE: To compare the effects on fat metabolism and Kupffer cell morphology by total parenteral nutrition (TPN) with two different fat emulsions. DESIGN: Thirty-two male Sprague-Dawley rats, divided into three groups, were investigated. Rats fed orally were used as a reference group, and a group of rats receiving TPN with fat emulsions containing pure long-chain triglycerides (LCT) was compared to a group of rats receiving fat emulsions containing both long-chain triglycerides and medium-chain triglycerides (MCT/LCT). The TPN regimens were equicaloric and administered continuously via a jugular catheter for 10 days. INTERVENTIONS: After suffocation, blood of the rats was collected for the determination of serum lipids. Epididymal fat and heart were collected for the analysis of lipoprotein lipase (LPL) activities, and liver specimens were saved for analyses of hepatic triglyceride concentration, as well as activities of hepatic lipase (HL) and lysosomal enzymes. Light and electron microscopy were used for examination of the Kupffer cell reaction. RESULTS: Directly after termination of parenteral feeding, the levels of serum triglycerides and high density lipoprotein (HDL) triglycerides were higher in the MCT/LCT group than in the LCT group, while no differences concerning cholesterol and phospholipid concentrations were found. No significant difference in liver steatosis was found between the two TPN groups. Comparison of the TPN groups showed that the MCT/ LCT group had significantly decreased LPL activity in adipose tissue, while the LCT group had significantly increased LPL activity in the heart. The activity of HL was low in both groups, but significantly lower in the LCT group. Lipid accumulation and an increased number of lysosomes were found in all Kupffer cell when TPN with LCTemulsions was used. Moreover, TPN induced a pronounced increase in various liver lysosomal enzyme activities, but there was no notable difference between LCT and MCT/LCT effects. CONCLUSIONS: Compared to treatment with pure LCTemulsions, treatment with MCT/LCT emulsions evoked weaker biochemical reactions in terms of lower activity of lipoprotein lipase in fat and heart together with higher serum and HDL triglyceride levels. Morphological signs of increased Kupffer cell activity such as the appearance of multiple lysosomes and fat vacuoles in the cytoplasm followed treatment with pure LCT emulsions. However, both TPN groups showed a marked increase in activities of liver lysosomal enzymes.

Animals↗
PubMed1998

Reduced neuronal activity and reactivation in Alzheimer's disease.

1. Alzheimer's disease is a multifactorial disease in which age and APOE-epsilon 4 are important risk factors. Various mutations and even viral infections such as herpes simplex (Itzhaki et al., 1997) may play an additional role. 2. The neuropathological hallmarks of Alzheimer's disease (AD), i.e. amorphous plaques, neuritic plaques (NPs), pretangles, neurofibrillary tangles (NFT) and cell death are not part of a single pathogenetic cascade but are basically independent phenomena. 3. Pretangles can occur in neurons from which the metabolic rate is not altered. However, in brain areas where classical AD changes, i.e. NPs and NFTs, are present, such as the CA1 area of the hippocampus, the nucleus basalis of Meynert and the tuberomamillary nucleus, a decreased metabolic rate is found. Decreased metabolic rate appears to be an independent phenomenon in Alzheimer's disease. It is not induced by the presence of pretangles, NFT or NPs. 4. Decreased metabolic rate may precede cognitive impairment and is thus an early occurring hallmark of Alzheimer's disease, which, in principle, may be reversible. The observation that the administration of glucose or insulin enhances memory in Alzheimer patients also supports the view that Alzheimer's disease is basically a metabolic disease. Moreover, several observations indicate that activated neurons are better able to withstand aging and AD, a phenomenon paraphrased by us as "use it or lose it". It is, therefore, attractive to direct the development of therapeutic strategies towards restimulation of neuronal metabolic rate in order to improve cognition and other symptoms in Alzheimer's disease. A number of pharmacological and non-pharmacological studies support the concept that activation of the brain indeed has beneficial effects on several aspects of cognition and other central functions.

Aging↗
PubMed1998

Signal transduction in islet hormone release: interaction of nitric oxide with basal and nutrient-induced hormone responses.

We examined the relation between the islet NO system and islet hormone secretion induced by either the non-glucose nutrient alpha-ketoisocaproic acid (KIC) or, in some experiments, glucose. KIC dose dependently stimulated insulin but inhibited glucagon secretion. In a medium devoid of any nutrient, the NO synthase (NOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) induced an increase in basal insulin release but a decrease in glucagon release. These effects were evident also in K+-depolarised islets. KIC-induced insulin release was increased by L-NAME. This increase was abolished in K+-depolarised islets. In contrast, glucose- induced insulin release was potentiated by L-NAME after K+ depolarisation. The intracellular NO donor hydroxylamine dose dependently inhibited KIC-stimulated insulin release and reversed KIC-induced suppression of glucagon release. Our data suggest that islet hormone secretion in a medium devoid of nutrients is greatly affected by the islet NO system, whereas KIC-induced secretion is little affected. Glucose-induced insulin release, however, is accompanied by increased NOS activity, the NOS-activating signal being derived from the glycolytic-pentose shunt part of glucose metabolism. The observed NO effects on islet hormone release can proceed independently of membrane-depolarisation events.

Animals↗
PubMed1998

The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester potentiates insulin secretion stimulated by glucose and L-arginine independently of its action on ATP-sensitive K+ channels.

The nature of the action of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on hormone release from isolated islets was investigated. We found that glucose-induced insulin release was potentiated by L-NAME in the absence or presence of diazoxide, a potent K+ATP channel opener, as well as in the presence of diazoxide plus a depolarizing concentration of K+. At a low, physiological glucose concentration L-NAME did not influence insulin secretion induced by K+ but inhibited glucagon secretion. L-arginine-induced insulin release was potentiated by L-NAME. This potentiation was observed also in the presence of K+ plus diazoxide. Further, glucagon release induced by L-arginine as well as by L-arginine plus K+ and diazoxide was suppressed by L-NAME. The results strongly suggest that the L-NAME-induced potentiation of insulin secretion in response to glucose or L-arginine as well as the inhibitory effects on glucagon secretion are largely mediated by L-NAME directly suppressing islet NOS activity. Hence NO apparently affects insulin and glucagon secretion independently of membrane depolarization events.

Adenosine Triphosphate↗
PubMed1998

Limited effect of neuritic plaques on neuronal density in the hippocampal CA1 area of Alzheimer patients.

Neurofibrillary tangles (NFTs) and neuritic plaques (NPs) are the classic neuropathological hallmarks of Alzheimer disease (AD). It is generally assumed that the pathogenic process of AD could start by local neurotoxicity induced by the beta-amyloid core of plaques, followed by the appearance of NFTs and eventually cell death. To determine whether or not local neurotoxicity around NPs is indeed a major pathogenetic mechanism, we used an image analysis system to measure the neuronal density around Bodian-stained NPs in the hippocampal CA1 area of eight AD patients. Neuronal density, as measured within two arbitrary concentric circles around NPs with a radius of 74 and 123.5 microm, respectively, was on average 19% and 16% lower than the density in similar control circles without NPs in the same section. Furthermore, neuronal density around NPs was inversely related to their size. To investigate the impact of such a local reduction in cell density around NPs on the entire CA1 area, we also determined the proportion of the CA1 covered by the NPs and the arbitrary concentric circles around them. This appeared to be 16.3% of the total CA1 area, which means that the negative effect of NPs on the cell density can only explain 2.6% of cell death in the entire CA area. In conclusion, this study suggests that although NPs have a local negative effect on neighboring neurons, their contribution to the strong decrease in CA1 cell numbers is limited.

Aged↗