iNOS gene deficiency modifies beta-amyloid deposition, cognitive performance and hippocampal long term potentiation in APPPS1 tg mice

The inducible form of the nitric oxide synthase (iNOS), is transcriptionally upregulated in response to inflammatory stimuli in Alzheimer's disease, potentially aggravating disease progression. In this study we determined the effect of iNOS deficiency in amyloid precursor protein/presenilin1 (APPPS1) transgenic mice on spatial memory, hippocampal long term potentiation (LTP), amyloid pathology, neuroinflammation and neuronal loss. APPPS1/iNOS (-/-) mice as well as APPPS1 mice treated with the iNOS inhibitor L-NIL, showed a significant reduction of working memory errors in the radial arm maze-test at 3 and 12 months of age as well as improvement of LTP at 3 months of age. Furthermore, APPPS1/iNOS(-/-) mice revealed decreased amyloid beta (Aß) burden at 12 months, as detected by thioflavin-S and Aß antibody immunostaining. Aß 1–40 and 1–42 levels in brain extracts of these mice were reduced as assessed by enzyme-linked immunosorbent assay. Immunohistochemical staining for glial fibrillary acidic protein and CD11b as well as RT-PCR for cytokines and chemokines also demonstrated that APPPS1/iNOS (-/-) mice had a reduced neuroinflammatory response. Neuronal cell loss was abrogated in the APPPS1/iNOS (-/-) mice. Preliminary data demonstrate that iNOS knockout in APPPS1 mice prevents early disturbances in posttranslational modifications of synaptic proteins and Aß degrading enzymes (nitratation, S-nitrosylation, phosphorylation).

These results suggest that iNOS expression aggravates AD-like neuropathological changes, cognitive performance and related electrophysiological parameters in an established animal model of AD. Since pharmacological iNOS inhibition showed similar if not identical effects than iNOS gene deficiency, iNOS may serve as a future therapeutic target in AD.