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(The FASEB Journal. 2000;14:1485-1489.)
© 2000 FASEB

Subacute NO generation induced by Alzheimer’s ß-amyloid in the living brain: reversal by inhibition of the inducible NO synthase

K. ISHII{dagger}, F. MUELHAUSER*, U. LIEBL*, M. PICARD{dagger}, S. KÜHL*, B. PENKE{ddagger}, T. BAYER§, M. WIESSLER{dagger}{dagger}, M. HENNERICI*, K. BEYREUTHER{dagger}, T. HARTMANN{dagger} and K. FASSBENDER*1

* Department of Neurology, Mannheim, University of Heidelberg, Germany;
{dagger} Center of Molecular Biology, ZMBH, University of Heidelberg, Germany;
{ddagger} Department of Medical Chemistry, Szeged, Albert Szent Gyorgyi Medical University, Hungary; and
§ Department of Psychiatry, University of Bonn, Germany; and
{dagger}{dagger} German Cancer Research Center, Heidelberg, Germany

1Correspondence: Department of Neurology Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68135 Mannheim, Germany. E-mail: Fass{at}neuro.ma.uni-heidelberg.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Glial activation contiguous to deposits of amyloid peptide (Aß) is a characteristic feature in Alzheimer’s disease. We performed complementary in vitro and in vivo experiments to study the extent, kinetics, and mechanisms of microglial generation of nitric oxide (NO) induced by challenge with Aß. We showed that Aß fibrils dose-dependently induced a marked release of stable metabolites of NO in vivo that was strikingly similar regarding extent and temporal profile to the one in the parallel designed microglial cell culture experiments. However, costimulation with interferon {gamma}, which was a prerequisite for Aß-induced NO generation in vitro, was not required in vivo, demonstrating that factors are present in the living brain that activate glial cells synergistically with Aß. Therefore, in Alzheimer’s disease, deposits of Aß fibrils alone may be sufficient to induce a chronic release of neurotoxic microglial products, explaining the progressive neurodegeneration associated with this disease. Our observation that systemic administration of selective iNOS inhibitors abolishes Aß-induced NO generation in vivo may have implications for therapy of Alzheimer’s disease.—Ishii, K., Muelhauser, F., Liebl, U., Picard, M., Kühl, S., Penke, B., Bayer, T., Wiessler, M., Hennerici, M., Beyreuther, K., Hartmann, T., Fassbender, K. Subacute NO generation induced by Alzheimer’s ß-amyloid in the living brain: reversal by inhibition of the inducible NO synthase.


Key Words: amyloid peptide • nitric oxide • iNOS • brain • in vivo microdialysis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
AMYLOID PEPTIDE (ASS), the cleavage product of amyloid precursor protein, is the major constituent of the senile plaques in Alzheimer’s disease (AD), the most common form of dementia in the elderly (1) . It is unknown, however, how the Aß pathology is linked to neurodegeneration associated with this demential disease.

Activated microglial cells and their products appear in large numbers at senile plaques of AD patients (2 , 3) and in mice overexpressing a mutant amyloid precursor protein gene (4) . These cells are crucial in host response to infection and injury (5) and have the potential to kill contiguous cells, including neurons, by release of highly cytotoxic products such as nitric oxide (NO) (6 , 7) .

In vitro, Aß possesses a pronounced synergistic effect on cytokine-induced activation of microglia or macrophages (7 8 9 10 11 12 13) . Aß can form long ß-pleated filaments. Such Aß fibrils have been demonstrated to bind to microglia via scavenger receptors (9) and receptors for advanced glycation end-products (10) , and have been shown to induce a more pronounced microglial activation than nonfibrillar peptide in vitro (9 , 11) .

Because these data suggest a pathogenetic role of inflammation in neurodegeneration of AD and since earlier epidemiological studies showed a protective effect of NSAID against later occurrence of dementia (14) , therapies directed against glial activation and concomitant release of toxic mediators are candidates for treating AD. However, further preclinical data are needed before such antiinflammatory strategies can be studied in the elderly with AD. In this study, we analyzed the extent and kinetics of glial NO generation on challenge with Aß not only in vitro, but also in the living brain, and investigated the effects of drugs to limit Aß-induced NO generation as a potential strategy to halt progression of AD.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Preparation and characterization of fibrillar Aß
Synthetic Aß (1–42) with known amino acid composition obtained from Botand Penke (Szeged, Hungary) and Bachem (Heidelberg, Germany) was dissolved in deionized water at a concentration of 1 mg/ml, vortexed, and immediately frozen in liquid nitrogen. To obtain fibrillar Aß (Fig. 1a, b ) vials were rapidly thawed and incubated for 7 days at 37°C. For in vivo applications, Speed VAC dried samples were resuspended in Ringer’s solution (pH 7.4).



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  		Figure 1. Electron microscopic analysis of nonfibrillar Aß (a) and fibrillar Aß. b) 5 µl of sample was placed on a carbon-coated Formvar-grid, diluted with 5 µl of 5% (v/v) glutaraldehyde solution, negatively stained with 5 µl of 2% (v/v) uranyl acetate solution, and examined using a Zeiss EM10 electron microscope (80,000x). Congo red staining of brain tissue was negative when nonfibrillar Aß was infused in brain (c) but positive on infusion of fibrillar Aß (d). For Congo red staining, the Accustain TM-Kit (HT60, Sigma), which included hematoxylin staining, was used (150x).

Primary microglial cultures and administration of Aß and test substances
Primary cultures of microglia were prepared from several brains of P1-P3 Balb/c mice as described earlier (15) . The purity of microglial cells was >95% as assessed by FACScan analyses with antibodies against MAC-1 and with isolectin B4. Briefly, after removal of the meninges, the brains were placed in tubes containing HBS solution and 1 ml 0.05% DNase and incubated at room temperature for 3 min. Suspended cells were incubated with 1% trypsin for 20 min at room temperature and collected by centrifugation for 10 min at 1000 g. After dissociation in HBS solution, the cells were collected, resuspended in Dulbecco’s modified Eagle medium supplemented with 10% heat-inactivated fetal bovine serum, and plated in a 75 cm2 culture flask. On days 14–21, cells located on the top layer were detached (shaking on a rotary shaker for 100 min at 200 rpm) and plated in 24-well tissue culture plates at 3.7 x 105 per 1 ml per well. The plates were incubated in the presence or absence of Aß with or without additional interferon {gamma} (IFN-{gamma}) (Sigma, St. Louis, Mo.), lipopolysaccharide (LPS) (E. coli, Sigma), the selective inhibitor of NO synthase (iNOS), L-N6-(1-iminoethyl)- lysine (L-NIL, Searle, St. Louis, Mo.), or the cyclooxygenase inhibitor indomethacin (Merck Sharp & Dohme, Haar, Germany). Media were changed daily and analyzed for NO2 content in order to characterize the temporal pattern of the cellular activation. Test substances (i.e., LPS+{gamma}-IFN, Aß+{gamma}-IFN, or indomethacin) were added once. In contrast, L-NIL was added for 1, 3, and 6 consecutive days since this drug is active for only a short time. Treatment of microglial cells with each of these substances had no effect on cell viability (as assessed by lactate dehydrogenase release).

In vivo microdialysis and administration of Aß and test substances
Male adult albino rats of a Wistar-derived strain (Charles River, Sulzfeld, Germany) weighing 250–320 g were anesthetized with 6% Nembutal 1 mg/kg intraperitoneal (i.p.) The tip of the microdialysis probe (CMA, Sweden) was intrahippocampally inserted (A-5.3 mm, L-5.2 mm, and V 6.6 mm with the incisor bar at -3.3 mm with respect to bregma and dural surface; ref 16 ). Aß peptides with or without IFN-{gamma} were administered using an injection cannula implanted contiguous to the microdialysis probe. Four days after stereotaxic intrahippocampal injection, fibrillar but not nonfibrillar Aß was recovered as Congo red-positive aggregates (Fig. 1c, d ). After surgery, the animals were housed individually with free access to food and water. Microdialysis was performed with a modified Ringer’s solution (pH 7.4) at a flow rate of 2 µl/min as described previously (17) . At this flow rate and at 37°C, we determined an in vitro recovery for nitrite/nitrate of 31 ± 2%. After a 2.5 h period of equilibration, dialysates were collected and frozen in intervals of 15 min for 2.5 h to obtain individual baseline values. After different treatments, perfusates were collected for 5 h on day 0 and (again after an initial equilibration interval of 2.5 h) on days 1, 2, and 3. Analogous to the in vitro experiments, the effects of L-NIL, indomethacin and IFN-{gamma} on Aß-induced nitrite/nitrate release were tested in vivo in dosages used in earlier animal studies.

Analysis of stable NO metabolites
The stable metabolites of NO, nitrite and nitrate, were quantified via the nitrite method using a colorimetric assay from Boehringer (Mannheim, Germany) (18) . The nitrate present in the sample was reduced to nitrite by reduced nicotinamide adenine dinucleotide phosphate in the presence of the nitrate reductase. The nitrite formed reacted with sulfanilamide and N-(1-naphthyl)-ethylenediamine dihydrochloride to yield a red-violet diazo dye, which was then quantified on the basis of its absorbance in the range of 550 nm. Known concentrations of sodium nitrite (1–100 µM) were included as standards. The limit of detection for nitrite was 0.28 µM. The intra- (inter-) test variance was less than 10% (20%).

Statistical analysis
Results were expressed as means (±SE). In microdialysis experiments, values were expressed as percentages of stable baseline values. The mean percent change of nitrite/nitrate formation was calculated for each day of examination. For nonparametric statistical analysis, the Mann-Whitney U test was used.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Kinetics of Aß-induced microglial NO generation in vitro and effects of pharmacological interventions
In microglial cells, Aß induced a marked release of nitrite/nitrate only synergistically with IFN-{gamma} (Fig. 2a ). Neither fibrillar Aß nor IFN-{gamma} alone was sufficient to elicit such a microglial response. The microglial response to a combined challenge with Aß and IFN-{gamma} occurred subacutely, peaking after 48 h. Thereafter, release of nitrite/nitrate tended to decline gradually until days 5–6 (Fig. 2a ). Fibrillar Aß/IFN-{gamma} elicited a stronger microglial response than nonfibrillar Aß/IFN-{gamma} on day 1 (P<0.01) and days 2–6 (P<0.0001, each, Fig. 2a ).



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  		Figure 2. In vitro experiments (n=4–6). a) Kinetics of NO2- production (±SE) in primary microglial cells after exposure with 50 µg/ml fibrillar Aß alone (F) or combined with 100 U/ml IFN-{gamma} (F+IFN), 50 µg/ml nonfibrillar Aß plus 100 U/ml IFN-{gamma} (NF+IFN), IFN-{gamma} alone (IFN), or 1 µg/ml LPS plus 100 U/ml IFN-{gamma} (LPS+IFN). b) Inhibition of NO2- release induced by fibrillar Aß plus IFN-{gamma} (F+IFN) by additional administration of 500 µM indomethacin (+IND) or 100 µM L-NIL for 1 (+LNIL1), 3 (+LNIL3), or 6 (+LNIL6) days.

L-NIL inhibited NO generation for 1 day (P<0.001) when administered to the medium once only, but for the entire study period (P<0.001) when added for 3 or 6 days (Fig. 2b ). Indomethacin significantly reduced release of NO metabolites on challenge with fibrillar Aß/IFN-{gamma} on days 1–5 (P<0.0001 each, Fig. 2b ).

Kinetics of Aß-induced intracerebral NO generation in vivo and effects of pharmacological interventions
Compared with control buffer or 1 mM nonfibrillar Aß, exposure to 1 mM fibrillar Aß (simulating the high local Aß concentrations in AD plaques; ref 19 ) significantly increased release of stable NO metabolites in vivo (P<0.05, Fig. 3a ). Effects of fibrillar Aß were dose-dependent, as injections of 0.1 mM Aß did not significantly increase nitrite/nitrate production (Fig. 3a ). Analogous to the in vitro experiments, NO metabolites were formed subacutely, with peak values after 24–48 h, and concentrations remained elevated for 72 h. Costimulation with IFN-{gamma}, which was a prerequisite for the ability of Aß to elicit NO generation in vitro, was not required in vivo; costimulation with this priming factor caused no further increase in Aß-induced NO generation (Fig. 3b ).



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  		Figure 3. In vivo experiments (n=6–7). a) Kinetics of NO2- release (±SE) after intrahippocampal administration (1 µl) of 1 mM (F) or 0.1 mM (F1/10) fibrillar Aß, 1 mM nonfibrillar Aß (NF), or Ringer’s solution (C) (percent change relative to individual baseline values, B). b) Effects of L-NIL (+LNIL, 2.5 mg in 0.5 ml PBS twice daily starting 2 days before microdialysis), indomethacin (+IND, 20 mg/kg, orally, twice daily starting 24 h before microdialysis), and IFN-{gamma} (+IFN, 120 U/µl, coinjected with Aß) on Aß-fibril- (F)- induced NO2- release.

L-NIL (5 mg/kg i.p., twice daily starting 48 h before microdialysis) significantly reduced NO generation after challenge with fibrillar Aß in vivo (P<0.05, Fig. 3b ). In contrast, indomethacin administrated twice daily via the clinically relevant oral route failed to significantly inhibit intracerebral release of NO metabolites in up to maximal nonlethal dosages (2x20 mg/kg/die p.o., beginning 24 h before microdialysis) (Fig. 3b ).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Using the in vivo microdialysis technique of the rat brain as a novel approach to investigate Aß-induced toxicity in vivo, we observed that Aß dose-dependently induced a subacute but sustained release of stable NO metabolites in the living brain. The extent and temporal profile of the marked response to Aß fibrils in vivo were strikingly similar to those observed in our parallel designed cell culture experiments. Both in vitro and in vivo fibrillar conformation of Aß was crucial for its ability to induce NO generation. However, a comparison between Aß-induced NO generation in vivo and in vitro allowed us to detect an important difference: in vitro, Aß activated microglial cells only synergistically with IFN-{gamma}, whereas in vivo Aß induced pronounced NO generation even in the absence of such an artificial costimulatory factor.

We observed in the in vitro model (murine microglial cell culture), but not in the in vivo model (rat), that IFN-{gamma} was a necessary costimulatory factor for Aß-induced NO generation. Since IFN-{gamma} also potentiates Aß-induced cellular activation in rat microglial cells (11 , 12) , differences between the in vitro and in vivo conditions rather than species-related differences may explain our observations. Thus, in the living brain, locally present mediators other than IFN-{gamma} may serve as costimulatory factors, explaining the observation that fibrillar Aß alone is sufficient to induce microglial activation in vivo.

Production of NO is catalyzed by three different isoforms of NOS. Our observation of suppression of NO generation by the selective inhibitor of iNOS, L-NIL, together with the delayed response kinetics characteristic of this inducible and protein synthesis-dependent isoform that is intracerebrally harbored chiefly in glial cells (20) , demonstrates that the iNOS is exclusively responsible for the Aß-induced NO generation in vitro and in vivo. These data therefore provide important complementary information to previous in vitro studies showing microglial activation by Aß (7 8 9 10 11 12 13) and histochemical studies showing glial activation (21) and expression of iNOS mRNA on intracerebral administration of Aß fibrils (22) .

Apart from microglia, however, monocytes recruited from the peripheral blood could contribute to intracerebral NO production. Indeed, the cerebral inflammatory host response is likely to be driven by both types of mononuclear phagocytes. Moreover, since astrocytes can be activated by microglial inflammatory cytokines (23) and can release NO (24) , it is possible that these cells represent an additional source of NO.

Whereas in low concentrations (nM range), NO plays a physiological role in neuronal signaling in high concentrations (µM range), this molecule possesses strong cytotoxic effects. Excessively produced NO, itself a free radical, promotes tissue injury, for example, by a reaction with superoxide anion to produce extremely toxic peroxynitrite or by interaction with additional proteins, transition metals, and iron/sulfur-containing or heme-containing compounds (25 , 26) . Is well known that uncontrolled release of NO by glial cells kills contiguous neurons (6) , and the overwhelming NO generation is discussed as a potential therapeutic target in several different pathological conditions (27 28 29) .

Our observation that the mere presence of fibrillar Aß in brain tissue induces NO generation (and possibly further toxic products) indicates that in AD patients, Aß deposits alone are sufficient to chronically induce neurotoxicity. Chronic release of toxic microglial products induced by progressive deposition of fibrillar Aß could therefore constitute the link between Aß pathology and the still unexplained neurodegeneration in AD. Consequently, Aß-induced glial NO generation represents an interesting therapeutical target. Our experiments show that the selective iNOS inhibitor L-NIL completely inhibited Aß generation not only in vitro, but also in the living organism. However, we were unable to observe an inhibitory effect of the indomethacin in vivo despite its obvious effectiveness in vitro.

It has to be noted that NO generation in rodents and humans may differ in extent. Human microglial cells may produce less NO than rodent microglia (30 , 31) . Although there are many indications for a pathophysiological role of NO in AD (32 33 34) , the relevance of the NO-mediated neurotoxicity in AD still has to be proved. However, as activated microglial cells corelease a large array of toxic products (free radicals, inflammatory cytokines, or toxic enzymes), NO generation assessed here as microglial activation markers reflects concomitant release of further cytotoxic microglial products that could play a detrimental role in human brain tissue.

In conclusion, the demonstration that Aß fibrils alone induce a subacute and sustained generation of NO in the living brain and that the selective iNOS inhibitor L-NIL is able to inhibit such response adds important evidence for a causal role of Aß-induced microglial toxicity in neurodegeneration in patients with AD and raises hope for novel strategies to halt the progression of this demential disease.

Received for publication August 24, 1999. Revision received January 14, 2000.
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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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K. Fassbender, M. Fatar, A. Ragoschke, M. Picard, T. Bertsch, S. Kuehl, and M. Hennerici
Subacute But Not Acute Generation of Nitric Oxide in Focal Cerebral Ischemia
Stroke, September 1, 2000; 31(9): 2208 - 2211.
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