Lack of association between clinical symptoms and postmortem indices of brain serotonin function in Alzheimer's disease.
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Aged↗
Biomedical subjects
V Haroutunian
Publications and source records attributed to V Haroutunian.
Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits.
Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimer's disease (AD) cases and controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin-releasing factor, serotonin, and 5-hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin-releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.
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Alterations in cerebral cortical galanin concentrations following neurotransmitter-specific subcortical lesions in the rat.
Galanin is associated with multiple projection neurons, and its immunoreactivity in the cerebral cortex may be derived from diverse sources. We investigated the effects of subcortical lesions on cerebral cortical galanin concentrations. Lesions of the anterior noradrenergic bundle (ANB) comparably reduced cerebral cortical galanin and norepinephrine (NE) concentrations. The effects of the ANB lesions on galanin were immediate and became most pronounced 1 week later. Extensive unilateral lesions of the nucleus basalis of Meynert (NBM) decreased galanin concentrations, although not as markedly as after ANB lesions. The NBM lesions had no additional effect in the presence of an ANB lesion. Decreases in cerebral cortical galanin concentrations depended upon the extent and the duration of the NBM lesion and were not as pronounced as the decreases in markers of cholinergic activity. Acute treatments with physostigmine, which inhibit cerebral cortical AChE, had no effect on galanin concentrations. The depletion of galanin following an NBM lesion was most pronounced within hours of the insult, while the depletion of ChAT following the same lesions required several days to develop. Cortical concentrations of galanin and 5-HT increased 1 hr after dorsal raphe nucleus (DRN) lesions and then decreased 7 d later. Six weeks later, galanin concentrations recovered in the cerebral cortex despite the continued depletion of 5-HT. These studies suggest that a substantial portion of cerebral cortical galanin may derive from noradrenergic neurons and may be modulated by cortically-projecting ACh and 5-HT neurons.
Animals↗
Chronic elevation of secreted amyloid precursor protein in subcortically lesioned rats, and its exacerbation in aged rats.
Subcortically lesioned rats were used as an animal model of some of the neurochemical and behavioral deficits of Alzheimer's disease (AD) to investigate the in vivo expression and metabolism of amyloid precursor protein (APP). Previously, the rapid and persistent induction of APP was described in cerebral cortices after disruption of its cholinergic, serotonergic, or noradrenergic afferents. In the present study, this induction was found to lead to the elevated secretion of APP into the cerebrospinal fluid of lesioned animals. Lesions of the forebrain cholinergic system in aged rats caused an even greater increase in the CSF levels of secreted APP. Antibodies to the extracellular domain of APP detected the protein whereas antibodies to the cytoplasmic region did not, indicating that the APP present in CSF was of the soluble form. Immunoprecipitation with an A beta sequence-specific antibody followed by immunoblot analysis indicated that a significant portion of secreted APP was of the species that contains at least the first 28 amino acids of the A beta sequence (APP gamma or APPA beta). By contrast, very low levels of A beta peptide were detected in CSF. The secretion was accompanied by an elevation of cellular C-terminal fragments of the APP in the lesioned cortex. Consistent with our previous results, this increased APP secretion was caused by lesions of subcortical cholinergic and serotonergic systems. The postlesion time course of APP secretion showed an initial reduction of APP (1 hr postlesion) in CSF followed by an eventual twofold elevation 1-6 weeks later. These results indicate that the induction of APP in response to loss of subcortical innervation leads to elevated secretion of a soluble form of cortically derived APP that contains significant portions of the A beta sequence.
Aging↗
Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer's disease.
Activity of the enzyme which synthesizes acetylcholine, choline acetyltransferase, was estimated in the neocortex of three series of control and demented cases. Clinically demented cases were divided into those with the classical neuropathological features of Alzheimer's disease (numerous neocortical plaques and tangles) and those with Lewy bodies in the brain stem and cortex (together with plaques and variable neurofibrillary pathology). In the Lewy body cases neocortical choline acetyltransferase was consistently lower than in the classical Alzheimer-type cases. Two of the Lewy body cases with extremely low cholinergic activity were responders in therapeutic trials of the cholinesterase inhibitor, tacrine, and the combined data suggest that cholinergic therapy may be particularly relevant to patients with Lewy body type dementia.
Alzheimer Disease↗
Cortical cholinergic markers in schizophrenia.
Cortical cholinergic deficits have been implicated in the cognitive deficits produced by a variety of neurodegenerative diseases including Alzheimer's disease (AD). Recent studies have suggested that many of the chronically institutionalized geriatric schizophrenic patients are also cognitively impaired. In this postmortem study we compared cholinergic marker activity in six different cortical regions derived from elderly controls, chronically institutionalized geriatric schizophrenic patients, and AD patients. All of the Alzheimer's disease cases met neuropathological criteria for AD, while none of the schizophrenic cases met criteria for AD. Cholinergic marker activity (choline acetyltransferase and acetylcholinesterase) was significantly diminished in the AD cohort but not in the schizophrenic cohort. Additionally, cortical choline acetyltransferase activity was significantly and negatively correlated with Clinical Dementia Rating scores (CDR), whereas no such correlations were evident in the schizophrenic cohort. These results suggest that cognitive deficits in geriatric schizophrenics are not due to diminished cortical cholinergic activity.
Acetylcholine↗
Characterization of gene expression in the cerebral cortices of rat brains containing subcortical lesions.
Neurotoxic lesion of the nucleus basalis of Meynert in the rat brain, which results in the loss of subcortical cholinergic innervation to the cerebral cortex, is an animal model for the cortical cholinergic deficits that are characteristic of Alzheimer's disease. Previously, we have shown that amyloid precursor protein is induced in the cortex in response to this disrupted innervation. We have investigated the synthesis and accumulation of proteins in lesioned versus control cortices. Total proteins from cortices were separated by high resolution two-dimensional gel electrophoresis and visualized by silver stain. Of the greater than 1,000 polypeptides examined, only one exhibited a consistent alteration in the lesioned sample. This unidentified protein (Mr 34 kD, pI 5.5) was normally present in scant amounts but was virtually absent in the lesioned cortex (0.056% total integrated density (TID) and 0.008% TID, respectively; p < 0.04). To investigate gene expression more directly, polysomes purified from lesioned and control cortices were assayed in vitro. Examination of [35S] incorporation into translation products by two-dimensional gels and autoradiography revealed three newly synthesized polypeptide differences in the lesioned samples. One protein (M(r) 47 kD, pI 6.1) exhibited elevated levels with the lesion (0.05% to 0.16%; p = 0.02) while two other proteins (M(r) 34 kD, pI 5.5, and M(r) 33 kD, pI 5.7) exhibited reduced levels (0.20% to 0.04%, p < 0.02, and 0.34% to 0.12%, p = 0.04, respectively).
Animals↗
Using the subcortically lesioned rat cortex to understand the physiological role of amyloid precursor protein.
Alzheimer's disease pathology is characterized by the presence of neuritic plaques and neurofibrillary tangles and specific neurotransmitter deficits in the cortex and hippocampus. Advances in the understanding of Alzheimer's disease have been hampered by the absence of appropriate animal model systems. Most in vivo rodent models have turned to aged animals, animals with experimentally induced lesions of various neurotransmitter systems, animals with pharmacologically induced neurotransmitter perturbations, and mice made transgenic for genes related to amyloid precursor protein. These models have been useful for the investigation of some discrete aspects of Alzheimer's disease, including deficits in forebrain cholinergic activity and the resulting cognitive deficits. However, none of these models have led to the development of the principal neuropathological hallmarks of Alzheimer's disease, neuritic plaques and neurofibrillary tangles. Furthermore, the relationship, if any, between the reduction of neurotransmitter activity and the formation of neuritic plaques and neurofibrillary tangles is unknown. The subcortically lesioned rat model system which we have used approximates the cortical neurotransmitter and the cognitive deficits of Alzheimer's disease. We have recently found that these same subcortical neurotransmitter system lesions alter the expression of amyloid precursor protein, the precursor of beta amyloid peptide, which is the principal component of neuritic plaques. Loss of functional subcortical innervation by either permanent lesions or transient inhibition of cortical neurotransmitter (acetylcholine) release resulted in the induction of amyloid precursor protein in the cortex. The induction was rapid and persistent with the permanent lesions or reversible with the transient inhibition. Lesions cholinergic, serotonergic,and adrenergic neurotransmitter systems all resulted in the induction.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Post-mortem examination of dopaminergic parameters in Alzheimer's disease: relationship to noncognitive symptoms.
Dopaminergic mechanisms have been implicated in depression, agitation, and psychosis--symptoms that are frequently observed in patients with Alzheimer's disease (AD). In a longitudinal study, 23 prospectively assessed AD patients underwent autopsies in which concentrations of dopamine, homovanillic acid, and dihydroxyphenylacetic acid were assayed in the temporal lobe (Brodmann areas 20 and 21). Data-reduction techniques were used to minimize the number of relationships tested. For this series of AD patients, no significant correlation was found between indices of dopaminergic neurotransmission and maximal severity of psychosis, depression, or agitation.
3,4-Dihydroxyphenylacetic Acid↗
Increased phosphorylation of elongation factor 2 in Alzheimer's disease.
Elongation factor 2 (EF-2) is a phosphoprotein that mediates the translocation step of elongation during protein synthesis. We investigated its phosphorylation to characterize translational regulation of gene expression in Alzheimer's disease. EF-2 was identified on two-dimensional (2D) gels of brain homogenates by analyzing immunoblots with EF-2-specific antibody (M(r) 96,000; pI 6.8). Four distinct charge variant isoforms were observed. We identified the two most acidic isoforms as being the phosphorylated forms by incorporation of radiolabeled phosphate. The phosphorylation of EF-2 in control and Alzheimer's disease (AD) brain was directly measured as the distribution of the four polypeptides on silver stained 2D gels. The ratio of the phosphorylated forms to unphosphorylated forms was elevated 45% in AD homogenates compared to controls (1.07 +/- 0.18; n = 9 vs 0.73 +/- 0.20; n = 6; P less than 0.004) which indicated an increased phosphorylation of AD EF-2. The phosphorylation exhibited specificity to the disease in that it was observed in affected areas (cortex and hippocampus) but not in an unaffected area (thalamus) of the same brains. Because phosphorylation of EF-2 inhibits protein synthesis, the observed AD-associated phosphorylation of EF-2 is consistent with the reduced in vitro activity of polysomes isolated from AD tissues that we have previously reported.
Adenosine Diphosphate Ribose↗
Increased synthesis and accumulation of heat shock 70 proteins in Alzheimer's disease.
Postmortem cortical tissues from Alzheimer's disease cases were found to contain significantly higher levels of the heat shock proteins hsp 72 and hsp 73 than control cortical tissues. This elevation was associated with the disease pathology in that it was not observed in Alzheimer's disease cerebella and was not correlated with perimortem characteristics such as age or cause of death of the patient or postmortem interval of the brain tissue. Examination of polysome translation products on two dimensional gels and by immunoprecipitation indicated that the syntheses of hsp 72/73 were increased in Alzheimer's disease tissues. In addition, immunoprecipitation of newly synthesized hsp 72 showed that numerous other nascent polypeptides were co-precipitated, which indicates an irreversible cotranslational association with the hsp 72. These results indicate that induction of specific heat shock proteins is associated with Alzheimer's disease and that cotranslational processes are affected by this induction.
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Increased biosynthesis of Alzheimer amyloid precursor protein in the cerebral cortex of rats with lesions of the nucleus basalis of Meynert.
The nucleus basalis of Meynert was lesioned by infusion of N-methyl-D-aspartate (NMDA) unilaterally in adult rat brain. Seven days post lesion we observed that polysomes isolated from the cerebral cortex affected by the lesion synthesized 2.6-fold greater amounts of the Alzheimer amyloid precursor protein (AAPP) compared to the nonlesioned side of the same rat brain. This increase exhibited specificity to AAPP in that overall protein synthesis was not altered by the lesion. The increase of AAPP did not alter the ratio of AAPP isotypes in rat brain (in which AAPP 695, which is lacking the protease inhibitor insert remains the predominant form). The increased synthesis did not result in the apparent accumulation of mature AAPP. These results indicate that a cholinergic lesion which models many of the neurochemical changes observed in Alzheimer's disease induces the expression of AAPP in a major projection region, the cerebral cortex.
Acetylcholinesterase↗
Reduced in vitro phosphorylation of synapsin I (site 1) in Alzheimer's disease postmortem tissues.
Homogenates prepared from the temporal cortex and hippocampus of individuals who had histopathologically confirmed Alzheimer's disease exhibited reduced in vitro cyclic AMP-dependent phosphorylation of synapsin I, neuronal phosphoprotein. One specific phosphorylation site (site 1) was affected while two other sites, which are phosphorylated by calcium/calmodulin kinase II, exhibited no such differences. Other phosphoproteins such as pyruvate dehydrogenase, did not show these differences. The reductions were not observed in either cerebellum or thalamus of Alzheimer's disease brain. Analysis by immunoblots indicated that the reductions were not caused by a decrease in absolute amounts of the protein. The reduced AD synapsin I phosphorylation was not overcome by the addition of purified cyclic AMP-dependent protein kinase. No differences were detected in total cyclic AMP-dependent protein kinase activity between the control and Alzheimer samples. However, dephosphorylation of the synapsin I prior to the in vitro phosphorylation reversed the differences observed between the control and AD homogenates. Thus, the reduced in vitro phosphorylation of the synapsin I in the Alzheimer homogenate reflects a reduced phosphorylatability of the protein due to either an increased phosphate content or some other alteration of the phosphorylation site.
Alzheimer Disease↗
Pharmacological alleviation of combined cholinergic/noradrenergic lesion-induced memory deficits in rats.
Data derived from a number of preclinical studies examining the effects of combined cholinergic and noradrenergic lesions in a rat model of Alzheimer's disease are reviewed. Results from these studies indicated that a nucleus basalis of Meynert (nbM) lesion combined with a lesion of the ascending noradrenergic bundle (ANB) did not exacerbate 72-h passive avoidance retention deficits beyond the degree of impairment produced by nbM lesions alone. However, the addition of an ANB lesion did block the efficacy of two choiinomimetics (physostigmine and oxotremorine) to reverse the lesion-induced memory impairment. Memory in combined lesioned rats was restored when cholinomimetic therapy was administered in combination with low doses of clonidine. Studies investigating a number of Hoechst-Roussel Pharmaceuticals compounds have produced memory-enhancing effects in animals prepared with combined nbM/ANB lesions without the need for clonidine supplementation. These compounds include P128, P86-7493, and P87-8184. Moreover, these compounds have also been shown to be effective in reversing passive avoidance memory deficits in animals with nbM lesions and treated with the noradrenergic toxin DSP-4. Implications for pharmacotherapeutic approaches for the treatment of Alzheimer's disease are discussed.
Alzheimer Disease↗
Fetal transplant-induced restoration of spatial memory in rats with lesions of the nucleus basalis of Meynert.
Bilateral lesions of the nucleus basalis of Meynert (nbM) in rats produced mnemonic deficits when subjects were tested on tests of spatial memory over a period of 3 to 7.5 months postoperatively. The transplantation of cholinergic-rich, fetal ventral forebrain tissue to either two or four frontoparietal cortical sites normalized performance on the spatial memory tasks. However, which transplant condition yielded recovery depended upon the nature of the task and/or posttransplantation interval. When assessed 8 months following transplant surgery, cortical choline acetyltransferase and acetylcholinesterase activity levels in both transplant groups were comparable to those values found in sham-operated animals. These data indicate that fetal transplants can reverse the mnemonic deficits and restore cortical cholinergic neurochemical activity to near-normal levels in rats with nbM lesions.
Animals↗
Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats.
The effects of combined lesions of forebrain cholinergic and noradrenergic systems on memory and responsivity to the memory enhancing effects of cholinomimetics were investigated in rats. Forebrain noradrenergic deficits produced by the injection of 6-hydroxydopamine into the ascending noradrenergic bundle (ANB) blocked the ability of cholinomimetics such as physostigmine and oxotremorine to enhance retention test performance in nucleus basalis of Meynert lesioned rats. Low doses of the noradrenergic receptor agonist clonidine, when administered in conjunction with cholinomimetics reversed this blockade. These results suggest that combined cholinergic/noradrenergic therapy may be of value in the treatment of some Alzheimer's disease patients.
Acetylcholine↗
Neurofibrillary tangles, Alzheimer's disease and Lewy bodies.
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Alzheimer Disease↗
Frontal cortex as the site of action of physostigmine in nbM-lesioned rats.
The administration of a variety of cholinomimetic agents to nucleus basalis of Meynert-lesioned rats has been shown to alleviate their lesion-induced memory deficits. This experiment attempted to determine whether the frontal cortex was the site of the memory enhancing action of the cholinomimetic physostigmine. Different groups of rats received excitotoxic lesions of the basal forebrain, the frontal cortex or both. Immediately after one trial passive avoidance training, these rats were injected with either saline or a 0.06 mg/kg dose of physostigmine. Physostigmine enhanced the 72-hour retention test performance of sham-operated and basal forebrain-lesioned rats, but failed to affect the performance of rats with cortical lesions. These data were interpreted as consistent with the hypothesis that the memory-enhancing effects of physostigmine are at least partially mediated by the frontal cortex.
Acetylcholinesterase↗