How is the peptide Aβ toxic to neurons? Many possible answers have been proffered, to no consensus. In the July 7 Journal of Neuroscience, Roger Anwyl and colleagues from Trinity College, Dublin, Ireland, offer this clue: The gas nitric oxide (NO) mediates amyloid-β inhibition of long-term potentiation (LTP), they conclude.

At last year’s Society for Neuroscience annual meeting in New Orleans, Anwyl and colleagues reported that several kinases, including Cdk5 and p38MAP, may mediate the inhibition of LTP by Aβ (see ARF related news coverage of New Orleans). Now, having widened the search for likely accomplices, they find that inducible nitric oxide synthase (iNOS) is involved, too.

First author Qinwen Wang tested the effect of Aβ on LTP in medial perforant neurons in rodent dentate gyrus slices (these neurons are some of the earliest affected in Alzheimer’s disease). As reported previously (see, for example, ARF related news story), Wang found that synthetic Aβ42 significantly reduced LTP mediated by N-methyl-D-Aspartate receptors (NMDAR), but not NMDAR-independent LTP. Long-term depression was unaffected.

To elucidate what cells in the slices mediate the inhibition, Wang repeated the experiment but first perfused the tissue with minocycline. This drug is a powerful inhibitor of microglia, which have been documented as being central to the toxic effects of Aβ (see McDonald et al., 1997). Under these conditions, Aβ failed to inhibit NMDAR-dependent LTP, suggesting that microglia are indeed involved. But how?

To address this question, Wang and colleagues chose to focus on nitric oxide. Because NO is generated in microglia by inducible nitric oxide synthase (iNOS), the authors measured LTP in slices from iNOS knockout mice. LTP was normal in this genetic background, yet inhibition of LTP by Aβ was abolished. This finding, plus the failure of Aβ to inhibit LTP in tissue slices perfused with NOS inhibitors, strongly indicates a role for the gas in Aβ toxicity.

NO can yield the much more potent oxidant, peroxynitrite. Formation of peroxynitrite is accelerated in the presence of superoxide, leading the authors to examine the role of reactive oxygen species (ROS) in Aβ toxicity (see ARF related news story on the growing evidence linking ROS with AD and other neurodegenerative diseases). They found that in combination with superoxide dismutase and catalase, which together reduce superoxide to water, Aβ failed to inhibit LTP. Indeed, the peptide also had no effect on LTP if Wang perfused tissue slices with inhibitors of NADPH oxidase, a common source of superoxide in cells.

How does this tie in with the authors’ report in New Orleans, which was recently published (see Wang et al., 2004)? “Peroxynitrite probably results in the inhibition of LTP via oxidation/tyrosine nitration of a particular protein necessary for LTP induction,” the authors write. They further suggest that the kinases they previously identified may be the ones scuppered by such chemistry. However, previous data has suggested that NO activation of microglia causes a reduction in Aβ in vivo (see ARF related news story), so whether NO in microglia is good or bad remains to be seen.

Even so, one thing is sure: The results yet again point the finger at microglial involvement in Alzheimer’s disease. In fact, also in the July 7 Journal of Neuroscience, Dave Morgan and colleagues from the University of South Florida, Tampa, and Rinat Neuroscience Corporation, Palo Alto, California, report that Aβ antibodies can lead to activation of microglia and clearance of Aβ from the brain.

First author Donna Wilcock and colleagues passively immunized Tg2576 transgenic animals, which express an amyloidogenic mutant of human Aβ precursor protein (AβPP). They gave the mice twice-weekly injections of Aβ antibodies and measured their progress with cognitive and physiological tests. Wilcock found that the immunization resulted in a noticeable reduction in both diffuse and compact amyloid brain deposits. Three months of treatment halved the amount of total Aβ and the number of congophilic plaques in mouse hippocampus, for example. These reductions were accompanied by increases in serum Aβ, consistent with the “peripheral sink” hypothesis for how passive immunity helps clear plaques (see ARF related news story). The mice also improved their scores in behavioral tests. Drug companies are intensely pursuing passive immunization strategies; Elan, for example, announced in a press release earlier this year that they had begun a phase 1 trial for such a vaccine.

As for the microglia connection, Wilcock found a dramatic increase in expression of antibody receptors on microglia following immunization. A month after the procedure started, she found that high-affinity receptors for IgG1 and IgG2a were elevated over sixfold. These receptors have been implicated in ingestion of Aβ deposits (see ARF related news coverage of Wilcock and Morgan’s New Orleans presentation). In addition, levels of CD45, a protein-tyrosine phosphatase, were also elevated following immunization. Activation of microglia is known to be stimulated by increased dephosphorylation by this enzyme.—Tom Fagan

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References

News Citations

  1. New Orleans: Aβ Oligomers and Memory: …Now They Are Bad
  2. Earliest Amyloid Aggregates Fingered As Culprits, Disrupt Synapse Function in Rats
  3. Aβ Production Linked to Oxidative Stress
  4. NO-Releasing NSAID Reduces b-Amyloid, Activates Microglia
  5. Two Ways to Attack Amyloid: Metal Chelator and Antibody
  6. New Orleans: Immunotherapy—The Game Is Still in Town

Paper Citations

  1. . Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. J Neurosci. 1997 Apr 1;17(7):2284-94. PubMed.
  2. . Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well a. J Neurosci. 2004 Mar 31;24(13):3370-8. PubMed.

Further Reading

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Primary Papers

  1. . Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J Neurosci. 2004 Jul 7;24(27):6049-56. PubMed.
  2. . Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J Neurosci. 2004 Jul 7;24(27):6144-51. PubMed.