Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease

doi:10.1084/jem.184.4.1425

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Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease

Y Vodovotz, MS Lucia, KC Flanders, L Chesler, QW Xie, TW Smith, J Weidner, R Mumford, R Webber, C Nathan, AB Roberts, CF Lippa and MB Sporn
Laboratory of Chemoprevention, National Institutes of Health, Bethesda, Maryland 20892, USA.

In Alzheimer's disease (AD), affected neurons accumulate beta amyloid protein, components of which can induce mouse microglia to express the high-output isoform of nitric oxide synthase (NOS2) in vitro. Products of NOS2 can be neurotoxic. In mice, NOS2 is normally suppressed by transforming growth factor beta 1 (TGF-beta 1). Expression of TGF-beta 1 is decreased in brains from AD patients, a situation that might be permissive for accumulation of NOS2. Accordingly, we investigated the expression of NOS2 in patients with AD, using three monospecific antibodies: a previously described polyclonal and two new monoclonal antibodies. Neurofibrillary tangle-bearing neurons and neuropil threads contained NOS2 in brains from each of 11 AD patients ranging in age from 47 to 81 years. NOS2 was undetectable in brains from 6 control subjects aged 23-72 years, but was expressed in small amounts in 3 control subjects aged 77-87 years. Thus, human neurons can express NOS2 in vivo. The high-output pathway of NO production may contribute to pathogenesis in AD.
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