[Epidemiological characteristics of Yersinia enterocolitica in patients with diarrhea from 2013 to 2019 in Pudong New Area, Shanghai].

Objective: To investigate the epidemiological characteristics of Yersinia enterocolitica in patients with diarrhea in Pudong New Area, Shanghai. Methods: Active surveillance of diarrhea was conducted in 14 sentinel hospitals (three tertiary-level hospitals, nine secondary-level hospitals, and two primary-level hospitals) from January 2013 to December 2019 in Pudong New Area of Shanghai, China base on their location, catchment area, and patient volume. Cold enrichment method was used to isolate Y. enterocolitica and further detection of bioserotype, virulence genes and antimicrobial susceptibility of the isolates were conducted. The difference of rates was determined using chi-square test or Fisher's exact test. Results: A total of 12 941 diarrhea cases were included, and 0.7% (88/12 941) cases were confirmed with Yersinia enterocolitica infection. 67.0% (59/88) cases were single infection, 33.0% (29/88) cases were mixed infections. Detection rates of Y. enterocolitica increased annually (0.3%-1.2%) and were highest in children<5 years of age (1.1%, 37/3 218) and in spring (1.1%, 32/2 998) (χ2 were 18.64 and 9.76, respectively, P<0.05). 58.0% (51/88) cases had watery diarrhea, 15.9% (14/88) had fever and 14.8% (13/88) had vomiting. The predominant bioserotypes were 3/O:3 (53.4%, 47/88), followed by 1A/O:8 (15.9%, 14/88) and 1A/O:5(6.8%, 6/88), respectively. Bioserotype 3/O:3 counted for the highest proportions (89.2%, 33/37) in children <5 years of age. All the strains of bioserotype 3/O:3 harbored ail, ystA, yadA and virF genes, which encoded pathogenic Y. enterocolitica. 11/14 strain of 1A/O:8 and 4/6 strains of 1A/O:5 harbored ystB gene. Most strains were resistant to ampicillin (80.7%,71/88) and amoxicillin/clavulanic acid (71.6%,63/88), and 63.8% (56/88) strains were multidrug resistance (MDR). The difference of antimicrobial resistance rates between 3/O:3 and non 3/O:3 was statistically significant in ampicillin, cefoxitin, nalidixic acid, tetracycline and ampicillin/sulbactam (χ2 was 14.68, 43.80, 41.86, 30.54 and 5.07, respectively, P<0.05). Conclusion: The detection rate of Yersinia enterocolitica was higher in children than in adults in Pudong New Area, Shanghai. The predominant bioserotype was pathogenic 3/O:3 with multidrug resistance.

Changes of blood pressure, serum inflammatory factors and endothelin levels in patients with hypertension under rehabilitative aerobic exercise.

The aim of this study was to evaluate the effects of rehabilitative aerobic exercise on blood pressure, serum inflammatory factors, endothelin and quality of life in patients with hypertension. Ninety patients with mild hypertension visiting West China Hospital of Sichuan University from June 2017 to December 2017 were enrolled and randomly divided into an experimental group and a control group. Patients in both groups were given a low-salt diet, and the experimental group was given an extra three-month treadmill training. Systolic blood pressure (SBP), diastolic blood pressure (DBP), serum tumor necrosis factor α (TNF-α), serum interleukin-6 and endothelin-1, body mass index (BMI), triglyceride (TG) and other indicators were examined in both groups before and after exercise, SF-36 scale was used to evaluate the quality of life. The results showed that after 3 months of exercise, SBP and DBP in the experimental group were significantly lower than those in the control group (P less than 0.05). Compared with the control group, the concentrations of TNF-α, interleukin-6 and endothelin-1 in the experimental group were significantly decreased (P less than 0.05). Correlation analysis showed that IL-6 was positively correlated with SBP (P less than 0.05), and TNF-α and ET-1 were positively correlated with diastolic blood pressure (P less than 0.05). The general health status, energy, mental health, social function, emotional function and health changes of the experimental group were significantly improved compared with before exercise (P less than 0.05). In conclusion, rehabilitative aerobic exercise can lower blood pressure and improve the overall quality of life in mild hypertension patients by inhibiting vascular inflammation and lowering plasma endothelin-1.

MicroRNA-139 modulates Alzheimer's-associated pathogenesis in SAMP8 mice by targeting cannabinoid receptor type 2.

Alzheimer's disease (AD) is a neurodegenerative disorder, and is the most common type of dementia in the elderly population. Growing evidence indicates that microRNAs (miRNAs) play a crucial role in neuroinflammation associated with AD progression. In this study, we analyzed the expression of microRNA-139 (miR-139) as well as the learning and memory function in AD. We observed that the miR-139 expression was significantly higher in the hippocampus of aged senescence accelerated mouse prone 8 (SAMP8) mice (2.92 ± 0.13) than in the control mice (1.49 ± 0.08). Likewise, the overexpression of miR-139 by means of hippocampal injection impaired the hippocampus-dependent learning and memory formation. In contrast, the downregulation of miR-139 in mice improved learning and memory function in the mice. The level of cannabinoid receptor type 2 (CB2), a potential target gene of miR-139, was inversely correlated with the miR-139 expression in primary hippocampal cells. Furthermore, we demonstrated that miR-139 inversely modulated the responses to proinflammatory stimuli. Together, our findings demonstrate that miR-139 exerts a pathogenic effect in AD by modulating CB2-meditated neuroinflammatory processes.

Study on transient photocurrent induced by energy level defect of schottky diode irradiated by high power pulsed laser.

The transient photocurrent is one of the key parameters of the spatial radiation effect of photoelectric devices, and the energy level defect affects the transient photocurrent. In this paper, by studying the deep level transient spectrum of a self-designed Schottky diode, the defect properties of the interface region of the anode metal AlCu and Si caused by high-temperature annealing at 150 â„ƒ, 200 â„ƒ and 300 â„ƒ for 1200 h have been quantitatively analyzed. The study shows that the defect is located at the position of + 0.41 eV on the valence band, the concentration is 2.8 [Formula: see text] 1013/cm2, and the capture cross section is [Formula: see text] = 8.5 [Formula: see text] 1017. The impurity energy level mainly comes from the diffusion of Al atom in anode metal. We found that the defect did not cause the electrical performance degradation and obvious morphology change of the device, but the transient photocurrent increased significantly. The reason is that the high temperature treatment results in a growth in the density of states at the interface between AlCu-Si. The more mismatched dislocations and recombination center increased the reverse current of the heterojunction. The above view is proved by the TCAD simulation test.

A recombinant metalloprotease antigen of Vibrio vulnificus elicits protective antibodies in a murine model.

AIMS: To investigate whether Vibrio vulnificus metalloprotease (VvpE) can induce the production of specific anti-VvpE antibody to confer effective protection against Vibrio vulnificus infection and to evaluate the possibility of VvpE as a potential vaccine candidate against disease caused by V. vulnificus. METHODS AND RESULTS: The gene encoding the 65-kDa VvpE of V. vulnificus was amplified by PCR and cloned into the expression vector pET21(b). The recombinant VvpE of V. vulnificus was expressed in Escherichia coli BL21(DE3). This His(6)-tagged VvpE was purified and injected intramuscularly into mice to evaluate its ability to stimulate immune response. Specific antibody levels were measured by ELISA. The 75% protective efficacy of recombinant VvpE was evaluated by active immunization and intraperitoneal challenge with V. vulnificus in mice. CONCLUSIONS: The recombinant His(6)-tagged VvpE of V. vulnificus is capable of inducing high antibody response in mice to confer effective protection against lethal challenge with V. vulnificus. VvpE might be a potential vaccine candidate to against V. vulnificus infection. SIGNIFICANCE AND IMPACT OF THE STUDY: This study uses His(6)-tagged VvpE to act as vaccine that successfully induces effective and specific anti-VvpE antibody and offers an option for the potential vaccine candidate against V. vulnificus infection.

[Antimicrobial resistance and molecular epidemiology of foodborne Yersinia enterocolitica in Pudong New District, Shanghai].

Objective: To investigate the antimicrobial resistance and molecular epidemiology of foodborne Yersinia (Y.) enterocolitica in Pudong New District of Shanghai. Methods: Four kinds of raw food samples were collected in retail circulation sites in Pudong from 2012 to 2016. Cold enrichment method was used to isolate Y. enterocolitica and further detection of biotype, serotype, virulent genes, antimicrobial susceptibility of the isolates and pulsed field gel electrophoresis (PFGE) were conducted. Results: A total of 3 900 raw food samples were collected during this period, including poultry product (n=590), livestock product (n=1 074), aquatic product (n=1 488), vegetable (n=748), in which 111 (2.8%) were contaminated by Y. enterocolitica. The detection rates of Y. enterocolitica in poultry product samples (5.3%, 31/590) and livestock product samples (4.5%, 48/1 074) were higher than those in aquatic product samples (1.6%, 24/1 488) and vegetable samples (1.1%, 8/748). The predominant biotype was 1A (95.5%) and predominant serotype was O∶8 (42.3%). All the strains lacked ail, ystA, yadA and virF genes, which encoded pathogenic Y. enterocolitica. Seventy six (68.5%) strains harbored ystB gene, in which 35 (31.5%) belonged to 1A/O∶8/ystB pattern. Most strains were resistant to ampicillin (74.8%) and amoxicillin/clavulanic acid (70.3%), and non-sensitive rate to Cefoxitin was over 50.0%. No third generation cephalosporin or fluoroquinolone resistant strains were detected, but 38.7% (43/111) strains were multidrug resistant (MDR). Serotype O∶8 and O∶5 strains had 44 and 18 PFGE patterns, respectively. Conclusions: The main foodborne exposure sources of Y. enterocolitica in raw food were poultry and livestock products in Pudong New District. 1A/O∶8/ystB was the predominant pattern with potential pathogenicity despite lacks of typical pathogenic virulent genes. The antimicrobial resistant rates of Y. enterocolitica were at a low level, but MDR strains still existed. Molecular types of the isolates showed highly genetic diversity.

Altered p-JAK1 expression is associated with estrogen receptor status in breast infiltrating ductal carcinoma.

The mammalian Janus kinase (JAK) family consists of four members, namely JAK1, JAK2, JAK3 and TYK2, which play a critical role in cytokine/growth factor signaling and is increasingly associated with human cancers. Aberrant activation of these non-receptor tyrosine kinases may contribute to carcinogenesis. Herein, we focused on exploring the potential role of p-JAK1 in breast cancer. The expression profiles of p-JAK1 were analyzed in 68 pairs of cancer and non-cancer breast tissues from the same infiltrating ductal carcinoma case by using immunoblotting technique. The results obtained were further correlated with clinicopathological characteristics. Intriguingly, p-JAK1 expression was decreased in 55.9% of breast cancer tissues as compared to the matched non-cancer tissues. Further immunohistochemistry study showed an intense p-JAK1 staining predominantly in adjacent normal breast tissues but not the matched cancer lesions. Decreased p-JAK1 expression in breast cancer tissues was significantly correlated with positive estrogen receptor (ER) status and increased tumor size (p=0.010 and 0.009). We also found that p-JAK1 expression was high in ERalpha-negative breast cancer cell lines but was low in ERalpha-positive breast cell lines. Transfection of ERalpha-positive MCF-7 cells with an ERalpha-specific siRNA upregulated the expression of p-JAK1. In summary, our results indicated that an altered p-JAK1 expression might be involved in the development of breast infiltrating ductal carcinoma in an ERalpha-related manner.

Effect of HCH contamination of diet on the growth performance and immune and antioxidant ability in growing/finishing pigs.

The effects of hexachlorocyclohexane (HCH) on growth performance and immune and oxidative stress in growing/finishing pigs were studied. Seventy-two pigs, with equal numbers of barrows and gilts, of the same genotype (Duroc x Landrace x Large White), were randomly assigned to three groups receiving the same basal diet, exposed to 0, 0.4 and 0.8 mg/kg technical HCH, respectively, for 90 days. Six pigs from each group were randomly picked out and slaughtered on a finishing feeding trial. The result showed that addition of HCH did not affect the growth performance significantly but increased the weight of kidney and thymus significantly. Total serum IgG and IgM were elevated significantly, but there were no significant differences in serum IgA, C3 and C4 among the groups. Addition of HCH to feedstuff reduced superoxide dismutase (SOD), glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GSH-Px) activities in liver, reduced serum catalase (CAT) activity, and increased serum malondialehyde (MDA). Moreover, the activities of serum alanine aminotransferase and alkaline phosphatase were increased significantly. Addition of 0.4 mg/kg or 0.8 mg/kg HCH did not affect the growth performance but affected the immune and antioxidant potential.

Bax protein expression is increased in Alzheimer's brain: correlations with DNA damage, Bcl-2 expression, and brain pathology.

We have shown that many neurons in Alzheimer's disease (AD) exhibit terminal deoxynucleotidyl transferase (TdT) labeling for DNA strand breaks, and upregulation of Bcl-2 is associated with neurons exhibiting nuclear DNA fragmentation, while downregulation of Bcl-2 is associated with tangle-bearing neurons in AD brains. Consequently, we examined the expression of bcl-associated X (Bax) protein in AD brain. Immunoreactivity for Bax was seen in neurons and microglia of the hippocampal formation, and was elevated in the majority of AD cases as compared to control cases. Interestingly, 3 transitional cases, which had mild degeneration changes, exhibited relatively high levels of Bax immunoreactivity. Most Bax-positive neurons showed either TdT-labeled nuclei or Bcl-2 immunoreactivity. Although Bax immunoreactivity was detected within most early tangle-bearing neurons, many Bax-positive neurons did not colocalize with later-stage tangle-bearing neurons. In regions containing relatively few tangles in mild AD brains, many TdT-labeled neurons were immunolabeled with Bax antibody and most of them lacked evidence of neurofibrillary changes. These findings suggest that Bax may contribute to neuronal cell death in AD. Furthermore, DNA damage and the upregulation of Bax appear to precede tangle formation or may represent an alternative pathway of cell death in AD.

Parallel compensatory and pathological events associated with tau pathology in middle aged individuals with Down syndrome.

Aged individuals with Down syndrome (DS) develop senile plaques and neurofibrillary tangles consistent with Alzheimer disease (AD). Prior to or in parallel with AD pathology, compensatory growth responses may occur. Immunohistochemistry and confocal microscopy studies in the hippocampus from 15 individuals ranging in age from 5 months to 67 years compared markers of normal and abnormal tau accumulation (phosphorylated tau [AT8, MC-1], tau-1, N-terminal tau) with the extent and location of neuronal growth marker immunoreactivity (BDNF, GAP-43, MAP-2). In middle age (30-40 years), prior to entorhinal neuron loss, the earliest tau accumulation occurred in the outer molecular layer (OML), which was consistent with both pathological and compensatory fetal tau expression. These events were followed at a later age, associated with entorhinal neuron loss, by an increase in GAP-43. Hilar neurons exhibiting a sprouting morphology were also noted. Age-dependent observations in the DS brain in the current study parallel hippocampal compensatory responses described in entorhinal cortex lesion studies in rodents. Thus, compensatory growth responses may occur in DS prior to extensive AD pathology and may be one mechanism underlying observations in PET studies of hypermetabolism in the entorhinal cortex of individuals with DS.

Mechanisms of neuronal death in Alzheimer's disease.

Recent data in cell culture has shown that brain neurons are particularly vulnerable to degeneration by apoptosis. Further the inducers that activate the program (e.g. beta-amyloid, oxidatative damage, low energy metabolism) correspond to conditions present in the Alzheimer's disease (AD) brain. This suggests the possibility that apoptosis may be one of the mechanisms contributing to neuronal loss in this disease. Indeed, some neurons in vulnerable regions of the AD brain show evidence of DNA damage, nuclear apoptotic bodies, chromatin condensation, and the induction of select genes characteristic of apoptosis in cell culture and animal models. This suggests the existence of apoptosis in the AD brain, a hypothesis also consistent with evolving research in one of the regulatory functions of the presenilin genes. On the other hand, DNA damage is present in the majority of neurons in vulnerable regions in early and mild cases. In most tissues, cells in fully activated apoptosis degenerate and are removed within hours to days and thus it seems all DNA damage is unlikely to signify terminal apoptosis. The presence of extensive DNA damage suggests an acceleration of damage, faulty repair process, loss of protective mechanisms, or an activation and arrest of aspects of the apoptotic program. DNA damage is unlikely to be an artifact of postmortem delay or agonal state. The existence of protective mechanisms for neurons may exist as these cells are nondividing and essential. In this context it is interesting that Bcl-2 is upregulated in most neurons with DNA damage. Further, at least one DNA repair enzyme is also upregulated. Thus it appears as if neurons are in a struggle between degeneration and repair. As research advances it is critical to reduce the stimuli that cause the neuronal damage and discover the key intervention points to assist neurons in the repair processes.

Astrocytes degenerate in frontotemporal dementia: possible relation to hypoperfusion.

To understand the extent and specificity of astrocyte pathology in sporadic frontotemporal dementia (FTD), we examined several FTD cases for molecular and morphologic characteristics of astrocyte degeneration. We quantified reactive and degenerating astrocytes in sections of frontal, temporal, parietal, and occipital cortex identified using glial fibrillary acidic protein (GFAP) immunoreactivity, terminal deoxynucleotidyl transferase (TdT) labeling, and morphological characteristics and compared them with nondemented, age-matched control brains. Conventional and confocal microscopy revealed that a subpopulation of GFAP(+) astrocytes exhibited positive TdT labeling and beading of their processes in the frontal, temporal, and parietal cortices in 5 of 7 FTD cases that also exhibited gliosis. This morphology was reproduced in cultured astrocytes using ischemic insults. Degenerating astrocytes in FTD correlated inversely with cerebral blood flow as measured by single photon emission computed tomography (SPECT) analysis of (133)Xe inhalation (r = 0.55, p < 0.05). Furthermore, areas of significant astrogliosis corresponded to areas of SPECT hypoperfusion, suggesting that astrocytes may be affected by or perhaps have a causal role in the disturbances of cerebral perfusion in FTD.

Beta-amyloid accumulation in aged canine brain: a model of early plaque formation in Alzheimer's disease.

We characterized eight aged beagles (maintained from birth in a laboratory colony) and one black Labrador using Bielschowsky's, thioflavine S, and Congo red staining, and antibodies to the beta-amyloid peptide, dystrophic neurites, and other plaque components. All plaques within these canine brains were of the diffuse subtype and were neither thioflavine S- nor Congo red-positive. The majority of plaques in the entorhinal cortex contained numerous neurons within them while plaques in the dentate gyrus did not. beta-Amyloid immunoreactivity was also present within select neurons and neuronal processes and was detected as a diffuse linear zone corresponding to the terminal fields of the perforant path. There was no significant correlation between extent of beta-amyloid accumulation and neuron number in entorhinal cortex. Neither tau-1, PHF-1, nor SMI-31-immunostaining revealed dystrophic fibers, confirming the classification of these plaques as diffuse. Canine plaques did not appear to contain bFGF- or HS-positive immunostaining. This may explain why neuritic involvement was not detected within these canine plaques. It is possible that the beta-amyloid within the canine brain has a unique primary structure or may not be in an assembly state that adversely affects neurons.

Gene expression of Alzheimer-associated presenilin-2 in the frontal cortex of Alzheimer and aged control brain.

The presenilin-2 (PS2) gene expression pattern in Alzheimer's disease (AD) and control brains was examined using nonradioactive in situ hybridization. Message for PS2 was primarily detectable in neurons, particularly in somal cytoplasm. Intense staining signal was most commonly found in large pyramidal neurons, whereas moderate or faint staining was usually present in smaller neurons. The pattern of PS2 gene expression exhibited a laminar distribution profile in the frontal cortex. A small subset of tangle-bearing neurons exhibited PS2 hybridization signal in AD. PS2 mRNA expression appeared correlated to a high degree with lipofuscin autofluorescence in a large subset of neurons.

Localization of heparan sulfate glycosaminoglycan and proteoglycan core protein in aged brain and Alzheimer's disease.

Two monoclonal antibodies, one which recognizes a glycosaminoglycan epitope present in heparan sulfate glycosaminoglycan and another which recognizes the core protein of a basement membrane heparan sulfate proteoglycan, were used to study the distribution and localization of these components in Alzheimer's disease and control brain. The cytoplasm of neurons, and occasional neurofibrillary tangles, senile plaques and astrocytes were immunopositive for the heparan sulfate glycosaminoglycan antibody in control brains. In Alzheimer's tissue, however, the number and intensity of these elements was more extensive than in control brains. In addition, within the Alzheimer's brains studied, the nuclei of select neurons and a small number of microglia were also immunopositive for heparan sulfate glycosaminoglycan in contrast to controls, where nuclei and neuroglia were immuno-negative. Some senile plaques in Alzheimer's tissue also contained strong heparan sulfate glycosaminoglycan-positive neurites which were not seen in controls. In Alzheimer's tissue, double labeling for heparan sulfate glycosaminoglycans and the beta-amyloid protein in adjacent sections revealed that, in general, heparan sulfate glycosaminoglycan- and beta-amyloid protein-immunopositive plaques were co-localized. Occasionally, however, beta-amyloid-positive plaques were seen without heparan sulfate glycosaminoglycan immunoreactivity and vice versa. Heparan sulfate glycosaminoglycan immunoreactivity and Tau immunoreactivity co-localized in many neurofibrillary tangles; however a small number of heparan sulfate glycosaminoglycan-positive neurofibrillary tangles did not co-localize with Tau-positive neurofibrillary tangles. In contrast, the heparan sulfate proteoglycan antibody immunostained only the walls of blood vessels and a few senile plaques in Alzheimer's brains and primarily blood vessels in control brains. Heparan sulfate glycosaminoglycan immunostaining was present within neurons, glia, neurofibrillary tangles and senile plaques in Alzheimer's tissue. These results suggest that heparan sulfate-like molecules play an important role in the pathogenesis of the characteristic lesions of Alzheimer's disease and could serve as a marker reflecting early pathological changes.

Aggregation of the amyloid precursor protein within degenerating neurons and dystrophic neurites in Alzheimer's disease.

Using a monoclonal antibody raised against purified, native, human protease nexin-2/amyloid precursor protein, which recognizes an amino terminal epitope on the amyloid precursor protein and detects all major isoforms of amyloid precursor protein, we examined the localization of the amyloid precursor protein within Alzheimer's and aged control brains. Very light cytoplasmic neuronal amyloid precursor protein staining but no neuritic staining was visible in control brains. In the Alzheimer's brain, we detected numerous amyloid precursor protein-immunopositive neurons with moderate to strong staining in select regions. Many neurons also contained varying levels of discrete granular, intracellular accumulations of amyloid precursor protein, and a few pyramidal neurons in particular appeared completely filled with amyloid precursor protein granules. "Ghost"-like deposits of amyloid precursor protein granules arranged in pyramidal, plaque-like shapes were identified. We detected long, amyloid precursor protein-immunopositive neurites surrounding and entering plaques. Many contained swollen varicosities along their length or ended in bulbous tips. Amyloid precursor protein immunoreactivity in the Alzheimer's brain was primarily present as granular deposits (plaques). The amyloid precursor protein granules do not appear to co-localize within either astrocytes or microglia, as evidenced by double-labeling immunohistochemistry with anti-glial fibrillary acidic protein and anti-leukocyte common antigen antibodies or Rinucus cummunicus agglutin lectin. Amyloid precursor protein could occasionally be detected in blood vessels in Alzheimer's brains. The predominantly neuronal and neuritic localization of amyloid precursor protein immunoreactivity indicates a neuronal source for much of the amyloid precursor protein observed in Alzheimer's disease pathology, and suggests a time-course of plaque development beginning with neuronal amyloid precursor protein accumulation, then deposition into the extracellular space, subsequent processing by astrocytes or microglia, and resulting in beta-amyloid peptide accumulation in plaques.

Early phosphorylation of tau in Alzheimer's disease occurs at Ser-202 and is preferentially located within neurites.

Within the neurofibrillary tangles (NFTs) and dystrophic neurites (DNs) of Alzheimer's disease (AD), the cytoskeletal protein tau is abnormally hyperphosphorylated. In this study we evaluate the phosphorylation of specific residues on tau within different phases of the formation of NFTs. Two monoclonal antibodies, AT8 and PHF-1, were used to selectively recognize phosphorylated Ser-202 and Ser-396 of PHF-tau protein, respectively. We found that abnormal phosphorylation of tau appears to occur first at Ser-202 in DNs, then at Ser-202 in the soma and finally at Ser-396 in DNs and NFTs. These results suggest that abnormal phosphorylation at Ser-202 of PHF-tau in DNs represents one of the earliest neuropathological changes within the neurites of vulnerable neurons and may have a pivotal role in the initial pathogenesis of AD.

Up-regulation of Bcl-2 is associated with neuronal DNA damage in Alzheimer's disease.

Cell death and neurofibrillary tangle formation are prominent features of Alzheimer's disease (AD). It has been suggested that DNA damage may reflect neuronal vulnerability. In this context, the Ced homologue Bcl-2 is able to repress a number of cell death programs. Recently we found both numerous nuclei exhibiting DNA damage within neurons in the AD brain and increases in Bcl-2 immunoreactivity. In this study, we examined the relationship between Bcl-2 expression and nuclear DNA damage or tangle formation. Nuclei exhibiting DNA damage were associated with an up-regulation of Bcl-2 expression, whereas tangle-bearing neurons were associated with a down-regulation of Bcl-2 expression.

Immunohistochemical evidence for apoptosis in Alzheimer's disease.

Recently, in vitro studies conducted in our laboratory and others have suggested that apoptosis may have a role in the neuronal cell death associated with Alzheimer's disease (AD). To evaluate this hypothesis, the hippocampi and entorhinal cortices of AD, aged control, and surgical biopsy tissue were examined using the ApopTag system for the detection of DNA fragmentation and DNA strains to reveal nuclear morphology. Numerous neuronal nuclei displaying distinct morphological characteristics of apoptosis were present within tangle-bearing neurons as well as non-tangle-bearing neurons in AD brain, whereas few or no such nuclei were detected in control brain. Our in vivo results support the hypothesis that apoptosis may be one mechanism leading neuronal cell death in AD.

Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer's disease brain.

The relationship of neuronal DNA damage to tangle-bearing neurons and nitrotyrosine (NT) expression, a neurochemical marker of oxidative damage mediated by peroxynitrite, was examined in visual cortex of AD patients. Many terminal deoxynucleotidyl transferase (TdT)-positive neurons were detected and the majority (93%) of these TdT-labeled neurons lacked evidence of tangle formation. NT expression was elevated in AD cases and most TdT-labeled nuclei also showed strong NT immunoreactivity. These data suggest the hypothesis that the neurons with DNA damage in the absence of tangle formation may degenerate by tangle-independent mechanisms and that oxidative damage may contribute to such mechanisms in AD.