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Suppression of neurocognitive damage in LP-BM5-infected mice with a targeted deletion of the TNF- gene

RYUICHI IIDA^*,,1, KUNIAKI SAITO^,12, KIYOFUMI YAMADA^*, ANTHONY S. BASILE^§, KENJI SEKIKAWA^¶, MASAO TAKEMURA, HIDEHIKO FUJII, HISAYASU WADA, MITSURU SEISHIMA and TOSHITAKA NABESHIMA^*2

^* Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan;
Gifu Research Laboratory, JBC, Inc., Gifu 503-0628, Japan;
Department of Laboratory Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan;
^§ Laboratory of BioOrganic Chemistry, NIDDK, Bethesda, Maryland 20892, USA; and
^¶ Department of Immunology, National Institute of Animal Health, Tsukuba 305-0856, Japan

²Correspondence: K.Saito, Department of Laboratory Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan. E-mail: saito{at}cc.gifu-u.ac.jp; or T.N., Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan. E-mail: tnabeshi{at}.med.nagoya-u.ac.jp

Brain levels of TNF- increase in many inflammatory conditions, including HIV-1 infection, and may contribute to neurodegenerative processes. The paucity of agents that can selectively and potently block TNF- processing or its receptors has led us to investigate the role of TNF- in chronic neurodegeneration associated with retroviral infection using mice with targeted deletions of the TNF- gene. Infection of wild-type C57BL/6 mice with the LP-BM5 murine leukemia retrovirus mixture leads to the development of a severe immunodeficiency as well as cognitive deficits and neuronal damage. TNF--(-/-) mice infected with LP-BM5 developed a systemic immunopathology indistinguishable in severity from that observed in contemporaneously infected wild-type mice. In contrast, the performance of infected TNF--(-/-) mice in the Y-maze and Morris water maze was not different from that of uninfected TNF--(-/-) mice. The extent of glial activation in the striatum, as indicated by the increase in density of peripheral benzodiazepine receptors, was equivalent in both groups of LP-BM5-infected mice. However, the decrease in striatal MAP-2 expression, a marker of neurodegeneration observed in infected wild-type mice, was not found in infected TNF--(-/-) mice. While the loss of TNF- appeared to have no effect on the course or severity of the central or peripheral immunopathology resulting from LP-BM5 infection, the behavioral and biochemical manifestations were substantially curtailed in the TNF--(-/-) mice. These findings directly support a role for TNF- in the neurodegenerative processes associated with viral infections such as HIV-1.—Iida, R., Saito, K., Yamada, K., Basile, A. S., Sekikawa, K., Takemura, M., Fujii, Wada, H. H., Seishima, M., Nabeshima, T. Suppression of neurocognitive damage in LP-BM5-infected mice with a targeted deletion of the TNF- gene.

Key Words: animal model • AIDS • TNF--(-/-) mice • dementia • learning • behavior

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