AD-associated Protein Research Articles

Screening for key genes associated with atopic dermatitis with DNA microarrays

The aim of the present study was to identify key genes associated with atopic dermatitis (AD) using microarray data and bioinformatic analyses. The dataset GSE6012, downloaded from the Gene Expression Omnibus (GEO) database, contains gene expression data from 10 AD skin samples and 10 healthy skin samples. Following data preprocessing, differentially expressed genes (DEGs) were identified using the limma package of the R project. Interaction networks were constructed comprising DEGs that showed a degree of node of >3, >5 and >10, using the Osprey software. Functional enrichment and pathway enrichment analysis of the network comprising all DEGs and of the network comprising DEGs with a high degree of node, were performed with the DAVID and WebGestalt toolkits, respectively. A total of 337 DEGs were identified. The functional enrichment analysis revealed that the list of DEGs was significantly enriched for proteins related to epidermis development (P=2.95E-07), including loricrin (LOR), keratin 17 (KRT17), small proline-rich repeat proteins (SPRRs) and involucrin (IVL). The chemokine signaling pathway was the most significantly enriched pathway (P=0.0490978) in the network of all DEGs and in the network consisting of high degree‑node DEGs (>10), which comprised the genes coding for chemokine receptor 7 (CCR7), chemokine ligand (CCL19), signal transducer and activator of transcription 1 (STAT1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1). In conclusion, the list of AD-associated proteins identified in this study, including LOR, KRT17, SPRRs, IVL, CCR7, CCL19, PIK3R1 and STAT1 may prove useful for the development of methods to treat AD. From these proteins, PIK3R1 and KRT17 are novel and promising targets for AD therapy.

Integration of genome-wide expression and methylation data: Relevance to aging and Alzheimer's disease

The progressive and latent nature of neurodegenerative diseases, such as Alzheimer's disease (AD) indicates the role of epigenetic modification in disease susceptibility. Previous studies from our lab show that developmental exposure to lead (Pb) perturbs the expression of AD-associated proteins. In order to better understand the role of DNA methylation as an epigenetic modifications mechanism in gene expression regulation, an integrative study of global gene expression and methylation profiles is essential. Given the different formats of gene expression and methylation data, combining these data for integrative analysis can be challenging. In this paper we describe a method to integrate and analyze gene expression and methylation arrays. Methylation array raw data contain the signal intensities of each probe of CpG sites, whereas gene expression data measure the signal intensity values of genes. In order to combine these data, methylation data of CpG sites have to be associated with genes.

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

Here we postulate that the adapter protein evolutionarily conserved signalling intermediate in Toll pathway (ECSIT) might act as a molecular sensor in the pathogenesis of Alzheimer's disease (AD). Based on the analysis of our AD-associated protein interaction network, ECSIT emerges as an integrating signalling hub that ascertains cell homeostasis by the specific activation of protective molecular mechanisms in response to signals of amyloid-beta or oxidative damage. This converges into a complex cascade of patho-physiological processes. A failure to repair would generate severe mitochondrial damage and ultimately activate pro-apoptotic mechanisms, promoting synaptic dysfunction and neuronal death. Further support for our hypothesis is provided by increasing evidence of mitochondrial dysfunction in the disease etiology. Our model integrates seemingly controversial hypotheses for familial and sporadic forms of AD and envisions ECSIT as a biomarker to guide future therapies to halt or prevent AD.

Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease

BackgroundRheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis.ResultsIn our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively).ConclusionsRA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression.

Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice

The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (Aβ) levels and Aβ plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Aβ-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and Aβ in the cortex of TASTPM but did not alter Aβ plaque load, presenilin 1, or β-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and Aβ likely as a result of enhanced β/γ secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD.

Emerging role of Alzheimer's disease-associated ubiquilin-1 in protein aggregation

Abnormal protein aggregation and intracellular or extracellular accumulation of misfolded and aggregated proteins are key events in the pathogenesis of different neurodegenerative diseases. Furthermore, endoplasmic reticulum stress and impairment of the ubiquitin-proteasome system probably contribute to neurodegeneration in these diseases. A characteristic feature of AD (Alzheimer's disease) is the abnormal accumulation of Abeta (amyloid beta-peptide) in the brain. Evidence shows that the AD-associated PS (presenilin) also forms aggregates under certain conditions and that another AD-associated protein, ubiquilin-1, controls protein aggregation and deposition of aggregated proteins. Here, we review the current knowledge of ubiquilin-1 and PS in protein aggregation and related events that potentially influence neurodegeneration.

Lifespan Profiles of Alzheimer's Disease-Associated Genes and Products in Monkeys and Mice

Alzheimer's disease (AD) is characterized by plaques of amyloid-beta (Abeta) peptide, cleaved from amyloid-beta protein precursor (AbetaPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 (SP1), and the beta amyloid precursor cleaving enzyme (BACE1). In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases.

Brain region-specificity of palmitic acid-induced abnormalities associated with Alzheimer's disease

BackgroundAlzheimer's disease (AD) is a progressive, neurodegenerative disease mostly affecting the basal forebrain, cortex and hippocampus whereas the cerebellum is relatively spared. The reason behind this region-specific brain damage in AD is not well understood. Here, we report our data suggesting "differential free fatty acid metabolism in the different brain areas" as a potentially important factor in causing the region-specific damage observed in AD brain.FindingsThe astroglia from two different rat brain regions, cortex (region affected in AD) and cerebellum (unaffected region), were treated with 0.2 mM of palmitic acid. The conditioned media were then transferred to the cortical neurons to study the possible effects on the two main, AD-associated protein abnormalities, viz. BACE1 upregulation and hyperphosphorylation of tau. The conditioned media from palmitic-acid treated cortical astroglia, but not the cerebellar astroglia, significantly elevated levels of phosphorylated tau and BACE1 in cortical neurons as compared to controls (47 ± 7% and 45 ± 4%, respectively).ConclusionThe present data provide an experimental explanation for the region-specific damage observed in AD brain; higher fatty acid-metabolizing capacity of cortical astroglia as compared to cerebellar astroglia, may play a causal role in increasing vulnerability of cortex in AD, while sparing cerebellum.

Two-dimensional electrophoresis analyses of atopic dermatitis and the chances to detect new candidate proteins by the variations in immobilized pH gradient strips

Proteomic approaches, one of the high-throughput technologies, have been used to search for the proteins that are abnormally expressed in human diseases. The atopic dermatitis (AD)-associated genes or proteins are gradually being reported. In accordance with recent reports, we conducted the serial proteomic studies to compare with the protein expression level and to find a critical protein associated with AD. We applied two-dimensional electrophoresis (2-DE) coupled with MADI-TOF as well as LC-MS/MS to detect dysregulated protein in the AD proteome obtained from the patient-derived primary cells. Real-time PCR was also conducted to compare with the proteomic results in the transcriptional level. We successfully detected new AD-associated proteins in the AD-derived fibroblasts 2D-PAGE studies due to the IPG strip variations after conducting MALDI-TOF mass spectrometry and identification of the proteins. From the real-time PCR quantifications, we found that the altered expression of caldesmon 1 isoform 5, nucleophosmin 1, esterase D and chloride intracellular channel 4 were well matched both at the transcriptional and translational levels, and this suggested that these proteins may have important involvement with the pathogenesis of AD. By simply repeating the trials with changing the commercial strips with different lot numbers in the 2D-PAGE analysis, this provided us with new finding in the AD-derived samples. This approach we used may increase the chances of finding new candidate proteins in the clinical samples and it may also be applicable for proteomic studies of other diseases.

Reticulons RTN3 and RTN4‐B/C interact with BACE1 and inhibit its ability to produce amyloid β‐protein

Beta-secretase beta-site APP cleaving enzyme 1 (BACE1), is a membrane-bound aspartyl protease necessary for the generation of amyloid beta-protein (Abeta), which accumulates in the brains of individuals with Alzheimer's disease (AD). To gain insight into the mechanisms by which BACE1 activity is regulated, we used proteomic methods to search for BACE1-interacting proteins in human neuroblastoma SH-SY5Y cells, which overexpress BACE1. We identified reticulon 4-B (RTN4-B; Nogo-B) as a BACE1-associated membrane protein. Co-immunoprecipitation experiments confirmed a physical association between BACE1 and RTN4-B, RTN4-C (the shortest isoform of RTN-4), and their homologue reticulon 3 (RTN3), both in SH-SY5Y cells and in transfected human embryonic kidney (HEK) 293 cells. Overexpression of these reticulons (RTNs) resulted in a 30-50% reduction in the secretion of both Abeta40 and Abeta42 from HEK293 cells expressing the AD-associated Swedish mutant amyloid precursor protein (APP), but did not affect Abeta secretion from cells expressing the APP beta-C-terminal fragment (beta-CTF), indicating that these RTNs can inhibit BACE1 activity. Furthermore, a BACE1 mutant lacking most of the N-terminal ectodomain also interacted with these RTNs, suggesting that the transmembrane region of BACE1 is critical for the interaction. We also observed a similar interaction between these RTNs and the BACE1 homologue BACE2. Because RTN3 and RTN4-B/C are substantially expressed in neural tissues, our findings suggest that they play important roles in the regulation of BACE1 function and Abeta production in the brain.

Two‐dimensional electrophoretic profiling of atopic dermatitis in primary cultured keratinocytes from patients

Recently, we reported altered protein expression in primary cultured fibroblasts from atopic dermatitis (AD) patients. As a sequential study, we conducted proteomic analysis of primary keratinocytes derived from AD patients to further identify AD-related proteins. Three pH ranges, 4-7, 6-9, and 7-11, were used to profile the altered protein expression in AD. We obtained 46 candidate spots from the 2-D gel image analysis: 18 proteins were up-regulated and 27 proteins were down-regulated. Among the several important candidate proteins, NCC27 showed the same profile of a defect in PTM in both AD-derived keratinocytes and fibroblasts. On the basis of current and previous reports, real-time PCR was performed on select candidate genes to compare RNA and protein expression levels in AD-derived keratinocytes and fibroblasts. Our results provide new clues to aid in understanding the mechanism of atopic alterations in keratinocytes and suggest new AD-associated proteins that are important in AD pathogenesis.

Lead (Pb) exposure and its effect on APP proteolysis and Aβ aggregation

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical manifestations appearing in old age, however, the initial stages of this disease may begin early in life. AD is characterized by the presence of excessive deposits of aggregated beta-amyloid (Abeta) peptides, which are derived from the beta-amyloid precursor protein (APP) following processing by beta-secretase and gamma-secretase. Recently, we have reported that developmental exposure of rats to Pb resulted in latent elevation of APP mRNA, APP, and Abeta in old age. Here we examined whether latent up-regulation in APP expression and Abeta levels is exacerbated by concurrent disturbances in APP processing or Abeta aggregation. Among the environmental metals tested, only Abeta solutions containing Pb promoted the formation of Abeta aggregates at nanomolar concentrations. The lifetime profiles of alpha-, beta-, and gamma-secretases remained constant in adult and aging animals, and developmental exposure to Pb did not alter them. Furthermore, the addition of various concentrations of Pb (0.1 to 50 microM) to cerebral cortical extracts derived from control animals also did not affect the proteolytic activities of these enzymes. Therefore, we propose that amyloidogenesis is promoted by a latent response to developmental reprogramming of the expression of the APP gene by early exposure to Pb, as well as enhancement of Abeta aggregation in old age. In rodents, these events occur without Pb-induced disturbances to the enzymatic processing of APP. The aforementioned results provide further evidence for the developmental basis of amyloidogenesis and late-life disturbances in AD-associated proteins by environmental agents.

Cloning and identification of a novel human gene PDLIM5, a homolog of AD-associated neuronal thread protein (AD7c-NTP).

A novel human gene cDNA was successfully cloned from the human fetal brain cDNA library constructed by our lab, and this gene was termed PDLIM5 after acquiring the agreement of HUGO. BLASTX searching revealed that the hypothetical protein is a homolog of AD-associated neuronal thread protein (AD7c-NTP), which is over-expressed in Alzheimer disease (AD) beginning early in the course of disease, and over-expression of the AD7c-NTP gene would cause neuritic sprouting and cell death. SMART analysis showed that both our predicted protein and AD7c-NTP comprise BCL domain (only contains BH1 and BH2 regions). RT-PCR experiment revealed that the expression level of PDLIM5 in brain, skeletal muscle, prostate, colon and leukocyte is obviously higher than that in other tissues.

Neuroprotection strategies: effect of vinpocetine in vitro oxidative stress models

Reactive oxygen species (ROS) play an important role in neuronal damage and death that occurs in several neurodegenerative disorders, namely in Alzheimer's disease (AD). The observation that ROS neutralization may slow or reduce the neurodegenerative process associated with those pathologies stimulates the development of new drugs, more efficient and well tolerated, with antioxidant properties. Vinpocetine [14-etoxicarbonyl-3alpha,16alpha-ethyl)-14,15-eburnamine], a vincamine derivative, efficiently protects cells from ROS attack. Recently, the protective effect of vinpocetine was demonstrated using in vitro models of oxidative stress induced by the oxidant pair ascorbate/Fe2+ and by synthetic peptides of the AD-associated b-amyloid protein (Abeta). Results obtained from these in vitro experiences support that additional clinical trials should be carried out using vinpocetine, or vinpocetine derivatives, in order to test its therapeutical or preventive effects in diseases where oxidative stress plays a crucial role.

Age-related changes of Alzheimer’s disease-associated proteins in cynomolgus monkey brains

We characterized senile plaques (SPs) immunohistochemically in cynomolgus monkey brains and also examined age-related biochemical changes of Alzheimer’s disease (AD)-associated proteins in these brains from monkeys of various ages. In the neocortex of aged monkeys (>20 years old), we found SPs but no neurofibrillary tangles (NFTs). Antibodies against β-amyloid precursor protein (APP) or apolipoprotein E (ApoE) stained SPs; however, the pattern of immunostaining was different for the two antigens. APP was present only in swollen neurites, but ApoE was present throughout all parts of SPs. Western blot analysis revealed that the pattern of APP expression changed with age. Although full-length APP695 protein was mainly expressed in brains from young monkeys (4 years old), the expression of full-length APP751 protein was increased in brains from older monkeys (>20 years old). Biochemical analyses also showed that levels of various AD-associated proteins increased significantly with age in nerve ending fractions. Both SP-associated (APP) and NFT-associated proteins (tau, activated glycogen synthase kinase 3β, cyclin dependent kinase 5, p35, and p25) accumulated in the nerve ending fraction with increasing age; however, we found no NFTs or paired helical filaments of tau in aged cynomolgus monkey brains. This age-related accumulation of these proteins in the nerve ending fraction was similar to that observed in our laboratory previously for presenilin-1 (PS-1). The accumulation of these SP-associated proteins in this fraction may be a causal event in the spontaneous formation of SPs; thus, SPs may be formed initially in nerve endings. Taken together, these results suggest that intensive investigation of age-related changes in the nerve ending and in axonal transport will contribute to a better understanding of the pathogenesis of neurodegenerative disorders such as AD.

Oxidative nerve cell death in Alzheimer's disease and stroke: antioxidants as neuroprotective compounds.

Many neurodegenerative disorders and syndromes are associated with an excessive generation of reactive oxygen species (ROS) and oxidative stress. The pathways to nerve cell death induced by diverse potential neurotoxins such as peptides, excitatory amino acids, cytokines or synthetic drugs commonly share oxidative downstream processes, which can cause either an acute oxidative destruction or activate secondary events leading to apoptosis. The pathophysiological role of ROS has been intensively studied in in vitro and in vivo models of chronic neurodegenerative diseases such as Alzheimer's disease (AD) and of syndromes associated with rapid nerve cell loss as occuring in stroke. In AD, oxidative neuronal cell dysfunction and cell death caused by protofibrils and aggregates of the AD-associated amyloid beta protein (Abeta) may causally contribute to pathogenesis and progression. ROS and reactive nitrogen species also take part in the complex cascade of events and the detrimental effects occuring during ischemia and reperfusion in stroke. Direct antioxidants such as chain-breaking free radical scavengers can prevent oxidative nerve cell death. Although there is ample experimental evidence demonstrating neuroprotective activities of direct antioxidants in vitro, the clinical evidence for antioxidant compounds to act as protective drugs is relatively scarce. Here, the neuroprotective potential of antioxidant phenolic structures including alpha-tocopherol (vitamin E) and 17beta-estradiol (estrogen) in vitro is summarized. In addition, the antioxidant and cytoprotective activities of lipophilic tyrosine- and tryptophan-containing structures are discussed. Finally, an outlook is given on the neuroprotective potential of aromatic amines and imines, which may comprise novel lead structures for antioxidant drug design.

Effects of Intrastriatal MPP+ Injection on the Expression of Alzheimer^|^apos;s Disease-Associated Proteins in Nigrostriatal Neurons

While evidence has pointed to β-amyloid precursor proteins (APP) as a factor involved in the pathogenesis of Alzheimer's disease (AD), recent studies have demonstrated that APP is neuroprotective in function. Our observations have also indicated an increase of APP in retinal neurons and Muller glia following axotomy, ischemia and excitatory insults. In this study, we investigate further the effect of 1-methyl-4-phenyl-pyridinium (MPP + ), a neurotoxic metabolite that selectively damages dopaminergic neurons and is considered to be a parkinsonism inducer, on the expression of APP- and AD-associated proteins in relation to neuronal death and glial response. One hour to 2 months after unilateral injection of MPP + (100 nmol) to the striatum in the rat, a significant increase in APP expression was observed in damaged regions and remote areas including the ipsilateral cortex, whereas no detectable changes were observed in the contralateral side of the brain. The immunoreactive pattern and time-dependent increase of AD associated proteins, i.e., tau, apolipo-protein E and presenilins, was similar to that of APP in the severely injured striatum and cortex. A colocalization of these proteins and OX-42-positive cells, a marker of microglia and macrophages, was observed as well. Although the number of dopaminergic neurons decreased significantly in the substantia nigra, presumably by retrograde degeneration, the immunoreactivities of AD-related gene products were not altered obviously in this area. Other AD-related gene products such as β-amyloid showed no detectable changes in the nigrostriatal pathway at any time after MPP + intoxication. These observations suggest that APP and several gene products are molecular markers of injured neurons and are capable of providing certain signals to neuronal survival or/and death, and that glial cells take part in producing abnormal amount of AD-associated proteins which may have pathological implications, and indirectly correlate with a parkinsonian condition.

The AD7C-NTP neuronal thread protein biomarker for detecting Alzheimer's disease

Dementia in Alzheimer's disease (AD) is ultimately due to cell loss mediated by several mechanisms including, apoptosis, impaired mitochondrial function, and possibly necrosis. A second major neuroanatomic correlate of dementia is aberrant cortical neuritic sprouting with abundant proliferation of dystrophic neurites. Early in vivo detection of AD will require non-invasive assays of highly sensitive and relatively specific biomarkers that reflect these fundamental abnormalities in cellular function. The AD-associated neuronal thread protein (AD7c-NTP) gene encodes an approximately 41 kD membrane-spanning phosphoprotein that causes apoptosis and neuritic sprouting in transfected neuronal cells. The AD7c-NTP gene is over-expressed in AD beginning early in the course of disease. In the brain, increased AD7c-NTP immunoreactivity is associated with phospho-tau-immunoreactive cytoskeletal lesions, but not with amyloid-? accumulations. The levels of AD7c-NTP in postmortem brain tissue correlate with the levels measured in paired ventricular fluid samples, suggesting that the protein is secreted or released by dying cells into cerebrospinal fluid (CSF). In this regard, elevated levels of AD7c-NTP can be detected in both CSF and urine of patients with early or moderately severe AD, and the CSF and urinary levels of AD7c-NTP correlate with the severity of dementia. The newest configuration of the AD7c-NTP assay, termed "7c Gold", has greater than 90% sensitivity and specificity for detecting early AD. The aggregate results from a number of studies suggest that AD7c-NTP is an excellent biomarker that could be helpful in the routine clinical evaluation of elderly patients at risk for AD.

Effects of glucocorticoids on oxidative stress-induced hippocampal cell death: implications for the pathogenesis of Alzheimer's disease.

Hippocampal neurons are among the first neuronal cells to degenerate in the brain of patients affected by Alzheimer's disease (AD). These neurons have endogenous glucocorticoid receptors (GRs) and are vulnerable to oxidative stress that has been implicated in the pathogenesis of AD. The activities of various steroids can have an impact on neuronal function and the sensitivity of neurons to different toxic insults. Here it is shown that glucocorticoids can enhance the oxidative cell death induced by the AD-associated amyloid beta protein and glutamate in mouse clonal hippocampal HT22 cells and in primary embryonal neurons from rat. Glucocorticoids may permanently suppress the activity of the transcription factor NF kappa B and may block endogenous NF kappa B-driven cell defense programs. Therefore, age-related alterations of glucocorticoid homeostasis appear to enhance GR activation and may render hippocampal neurons more vulnerable to oxidative insults.

Distribution of Alzheimer's disease-associated protein (ADAP) in 10 human brains.

ALZ50-based enzyme immunoassay was used to study distribution of Alzheimer's disease-associated protein (ADAP) in postmortem brain tissues of 5 Alzheimer's disease (AD) and 5 non-Alzheimer's disease (NAD) subjects. There are at least three AD-associated proteins, including A68. Levels are higher in brain regions with severe neuronal loss in AD: frontal, temporal, hippocampal cortex, and amygdala. No significant ADAP was found in the NAD samples (from 2 age-matched-1 clinically demented-and 3 younger subjects). ADAP levels in four regions of AD brains were not correlated to neuritic plaque count in corresponding regions of matching formaldehyde-fixed hemispheres.