Expression of apoptosis related proteins in brains of patients with Alzheimer's disease.

An increasing number of proteins are implicated in apoptosis and several of them have been shown to be altered in Alzheimer's disease (AD) brain. Because of this apoptosis is thought to be the underlying mechanism of neuronal cell loss in AD. To further substantiate this hypothesis we investigated the expression of a recently identified apoptosis related proteins and other apoptosis regulators in frontal cortex and cerebellum of AD by Western blot and enzyme-linked immunsorbent assay technique. Quantitative analysis revealed unaltered levels of Bax and RAIDD (Receptor interacting protein associated ICH-1 (caspase-2)/CED-3 (Caenorhabditis elegans death protease-3)-homologous protein with death domain) in both regions. ZIP (Zipper interacting protein) kinase, Bim/BOD (Bcl-2 interacting mediator of cell death/Bcl-2 related ovarian death gene) and p21 were significantly increased only in AD frontal cortex (P < 0.05, in all cases). Cerebellar Bcl-2 levels were significantly increased in AD (P < 0.01) while in AD frontal cortex, although the levels tended to increase did not reach significance level. The results indicate that apoptosis indeed account for the neuronal loss in AD. However, it does not seem to involve Bax and RAIDD.

Neuronal nicotinic receptors in dementia with Lewy bodies and schizophrenia: alpha-bungarotoxin and nicotine binding in the thalamus.

Neuronal nicotinic receptors have been implicated in schizophrenia on the basis of the high incidence of tobacco smoking in patients, abnormalities in cytisine and alpha-bungarotoxin (alphaBGT) binding in the hippocampus, and linkage between auditory P50 deficits and the region of chromosome 15 coding the alpha7 subunit. In another disease associated with psychosis, dementia with Lewy bodies (DLB), in which visual hallucinations predominate, reductions in nicotine binding have been identified in various cortical and subcortical regions. We investigated both alphaBGT and nicotine binding autoradiographically in different thalamic nuclei in autopsy brain tissue from patients with schizophrenia and DLB. AlphaBGT binding in the reticular nucleus was moderately reduced (25%) in schizophrenia and more extensively reduced (50%) in DLB. There were no significant alterations in nicotine binding in schizophrenia, and in DLB, a trend towards moderate reductions in most nuclei reached significance in the lateral dorsal nucleus. It is concluded that widespread abnormalities of thalamic nicotine are not implicated in schizophrenia or DLB, but that reticular alphaBGT binding may be involved to a lesser and greater extent in the pathophysiology or psychopathology of both disorders.

Serotonin (5-HT) in brains of adult patients with Down syndrome.

Down syndrome (DS) is a genetic disease with developmental brain abnormalities resulting in early mental retardation and precocious, age dependent Alzheimer-type neurodegeneration. Furthermore, non-cognitive symptoms may be a cardinal feature of functional decline in adults with DS. As the serotonergic system plays a well known role in integrating emotion, cognition and motor function, serotonin (5-HT) and its main metabolite, 5-hydroxyindol-3-acetic acid (5-HIAA) were investigated in post-mortem tissue samples from temporal cortex, thalamus, caudate nucleus, occipital cortex and cerebellum of adult patients with DS, Alzheimer's disease (AD) and controls by use of high performance liquid chromatography (HPLC). In DS, 5-HT was found to be age-dependent significantly decreased in caudate nucleus by 60% (DS: mean +/- SD 58.6 +/- 28.2 vs. Co: 151.7 +/- 58.4 pmol/g wet tissue weight) and in temporal cortex by about 40% (196.8 +/- 108.5 vs. 352.5 +/- 183.0 pmol/g), insignificantly reduced in the thalamus, comparable to controls in cerebellum, whereas occipital cortex showed increased levels (204.5 +/- 138.0 vs. 82.1 +/- 39.1 pmol/g). In all regions of DS samples, alterations of 5-HT were paralleled by levels of 5-HIAA, reaching significance compared to controls in thalamus and caudate nucleus. In AD, 5-HT was insignificantly reduced in temporal cortex and thalamus, unchanged in cerebellum, but significantly elevated in caudate nucleus (414.3 +/- 273.7 vs. 151.7 +/- 58.4 pmol/g) and occipital cortex (146.5 +/- 76.1 vs. 82.1 +/- 39.1 pmol/g). The results of this study confirm and extend putatively specific 5-HT dysfunction in basal ganglia (caudate nucleus) of adult DS, which is not present in AD. These findings may be relevant to the pathogenesis and treatment of cognitive and non-cognitive (behavioral) features in DS.

Expression of DNA excision-repair-cross-complementing proteins p80 and p89 in brain of patients with Down Syndrome and Alzheimer's disease.

Although deficient DNA repair was proposed for neurodegenerative disorders including Down syndrome (DS), repair proteins for nucleotide excision repair have not been studied in brain yet. As one of the hypotheses for the pathogenesis of brain damage in DS and Alzheimer's disease (AD), is oxidative stress, and cells of patients with DS were shown to be more susceptible to ionizing irradiation. We decided to study expression of excision repair-cross-complementing (ERCC) gene products, proteins 80 and 89, representatives of repair genes known to be involved in the repair of different types of DNA damage. ERCC2-protein 80 kDa and ERCC3-protein p89 were determined in five individual brain regions of controls, aged DS and AD patients. Although different in the individual regions, DNA repair proteins were consistently higher in temporal and frontal lobes of patients with DS and higher in all brain regions of patients with AD. Our results are the first to describe DNA repair gene protein patterns in human brain regions providing the basis for further studies in this area. We showed that DNA repair genes ERCC2 and ERCC3 (excision-repair-cross-complementing) for nucleotide excision repair were increased at the protein level with the possible biological meaning that this increase may be compatible with and indicate ongoing (oxidative?) DNA damage.

Evidence against increased glycoxidation in patients with Alzheimer's disease.

Neuropathological findings of Alzheimer's disease (AD) are intracellular (neurofibrillary tangles) and extracellular (senile plaques) filamentous protein aggregates. Non-enzymatic glycation has been proposed as a primary factor in this pathogenesis, leading to increased insolubility of tau protein and beta-amyloid. The aim of our study was to test the hypothesis that increased glycoxidation, i.e. increased levels of oxidized products from non-enzymatic glycation could be found in brains of patients with AD and of aged Down syndrome (DS) subjects with abundant AD-like neuropathological lesions. Frontal cortex specimens were assayed for pentosidine (Pent) and N-epsilon-carboxymethyl-lysine (CML) by reversed phase high performance liquid chromatographical methods. Pent and CML levels in AD (n = 10; Pent, 35.5 +/- 4.84 mumol/g wet-weight tissue; CML, 135.2 +/- 5.0 mumol/g wet-weight tissue) were comparable to DS (n = 9; Pent, 36.4 +/- 3.21; CML, 133.5 +/- 4.7) and controls (n = 10; Pent, 35.2 +/- 3.55; CML, 136.9 +/- 3.3). We conclude that the results are not compatible with the concept of increased glycoxidation in AD compared to normal aging.

Similar deficits of central histaminergic system in patients with Down syndrome and Alzheimer disease.

In order to study whether Alzheimer-like neuropathological changes involve the central histaminergic system we measured the concentration of histamine, its precursor histidine as well as the activity of histidine decarboxylase (HDC) and histamine-N-methyl-transferase (HMT) in frontal cortex of aging Down syndrome (DS) patients, Alzheimer patients and control individuals. The study populations were also investigated for choline acetyltransferase (ChAT) activity, since reduced ChAT activity is an established biochemical hallmark in DS and Alzheimer disease (AD). HDC and ChAT activity were reduced in brains of both DS and Alzheimer patients versus control patients. Additionally, we observed a significant decrease of histamine levels in the DS group. Histamine levels in AD brains tended to be decreased. Histidine concentrations and HMT activities were comparable between the three groups. Thus, our results for the first time show histaminergic deficits in brains of patients with DS resembling the neurochemical pattern in AD. Neuropathological changes may be responsible for similar neurochemical alterations of the histaminergic system in both dementing disorders.

Excitatory amino acids and monoamines in parahippocampal gyrus and frontal cortical pole of adults with Down syndrome.

Aspartate (ASP), glutamate (GLU), noradrenaline (NA), dopamine (DA) and its acidic metabolites DOPAC and HVA, serotonin (5-HT) and its metabolite 5-HIAA were simultaneously investigated in post-mortem tissue samples from right parahippocampal gyrus (temporal cortex) and frontal cortical pole (frontal cortex) of adults with Down syndrome (DS), and of neurologically healthy controls by use of high performance liquid chromatography (HPLC). In parahippocampal gyrus, ASP, GLU, NA, DOPAC and 5-HT levels were significantly decreased in patients with DS, compared to levels found in control subjects (approximately 50%). No significant changes were observed in frontal pole. ASP and GLU levels were significantly lower in parahippocampal gyrus than in frontal pole of DS, a regional distribution that could not be observed in control subjects. In conclusion, the results of this study suggest that the temporal cortex would be more affected than the frontal cortex in adult patients with DS, a finding in line with reports showing a marked hypometabolism and extensive cell loss in temporal cortex of DS, and with those showing that parahippocampal gyrus abnormality may correlate with the extent of mental retardation affecting this type of patients.

Polyamines in frontal cortex of patients with Down syndrome and Alzheimer disease.

Polyamines may play an important role in brain development, mature brain function and also in neurodegenerative conditions. We investigated polyamine levels in frontal cortex of human post-mortem brain samples of elderly patients with Down syndrome (DS), Alzheimer disease (AD) and normal controls by means of chromatographic separation after dansylation. Spermidine and spermine concentrations were markedly decreased in DS and AD. Polyamine levels were neither related to age and post-mortem interval nor to choline acetyltransferase activity, as indicator of neuronal loss. Our results support the idea that besides other neurotransmitter systems, endogenous polyamine levels are altered in dementing illnesses such as Alzheimer disease and Down syndrome.

Increased kynurenic acid levels and decreased brain kynurenine aminotransferase I in patients with Down syndrome.

Excitatory amino acid (EAA) receptors are central to brain physiology and play important roles in learning and memory processes. Kynurenic acid (KYNA), a metabolite of tryptophan in the brain blocks all three classical ionotropic EAA receptors and also serves as an antagonist at the glycine site associated with the N-methyl-D-aspartate receptor (NMDA) complex. We measured the endogenous levels of KYNA and activities of KYNA synthesizing enzymes kynurenine aminotransferase I (KAT I) and kynurenine aminotransferase II (KAT II) in the frontal and temporal cortex of elderly Down syndrome (DS) patients (aged 46-69 years). Compared with control specimens (0.21 +/- 0.06 pmol/mg tissue), the measurement of KYNA content revealed a significant 3-fold increase in frontal cortex of DS patients (0.67 +/- 0.13 pmol/mg tissue; p < or = 0.01). In temporal cortex KYNA levels were increased by 151% (p < or = 0.05) of control (0.41 +/- 0.09 pmol/mg tissue) Using crude cell free homogenate KAT's activities were determined in the presence of the 1 mM 2-oxoacid as a co-substrate at their pH optima of 10.0 for KAT I and 7.4 for KAT II. KATs activities in the presence of 1 mM pyruvate were 2.79 +/- 0.52 and 4.55 +/- 1.98 pmol/mg protein/h for KAT I and 0.98 +/- 0.07 and 1.09 +/- 0.14 pmol/mg protein/h for KAT II in frontal cortex and temporal cortex, respectively. When compared with the brain samples of controls the activity of KAT I was reduced in frontal cortex (9.8 +/- 2.4%; p < or = 0.01) and temporal cortex (25.8 +/- 6.4 %) of DS patients, while KAT II levels were within the normal range. Measurement of the neuronal, cholinergic marker choline acetyltransferase (ChAT) in the frontal cortex, revealed a significant reduction (36.6 +/- 4.3% of control; p < or = 0.01) in DS. Our data demonstrate the involvement of KYNA-metabolism in the cellular mechanisms underlying altered cognitive function in patients with DS. Although the localisation of both, KAT I and KAT II is not stated yet the reduction of KAT I may suggest impairment of KYNA metabolism in neuronal and/or nonneuronal compartments.

Inter-agency collaboration: teaching breast self-examination to black women.

Excessive breast cancer mortality and limited use of mammography among black women point to a need for breast cancer education and increased use of breast self-examination (BSE) and other screening procedures. The Illinois Cancer Council (ICC), a consortial comprehensive cancer center, and the Chicago Chapter of the National Black Nurses' Association (CCNBNA) developed and piloted an educational project to increase black women's knowledge about breast cancer and their use of BSE and other screening methods. This paper describes the steps leading up to this collaborative effort, the procedures necessary to implement it, the difficulties encountered, and the impact of the educational program on the CCNBNA nurses and the high risk, hard-to-reach, underserved women who participated. This program is offered as a model for a collaborative effort between a cancer center or other healthcare facility and a professional organization to address unmet community health needs.