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The Journal of Neuroscience, March 21, 2007, 27(12):3057-3063; doi:10.1523/JNEUROSCI.4371-06.2007

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Neurobiology of Disease
Minocycline Reduces Microglial Activation and Improves Behavioral Deficits in a Transgenic Model of Cerebral Microvascular Amyloid

Rong Fan,¹ Feng Xu,¹ Mary Lou Previti,¹ Judianne Davis,¹ Alicia M. Grande,² John K. Robinson,² and William E. Van Nostrand¹

Departments of ¹Medicine and ²Psychology, Stony Brook University, Stony Brook, New York 11794

Correspondence should be addressed to Dr. William E. Van Nostrand, Department of Medicine, HSC T-15/083, Stony Brook University, Stony Brook, NY 11794-8153. Email: william.vannostrand{at}stonybrook.edu

Cerebral microvascular amyloid ß protein (Aß) deposition and associated neuroinflammation is increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Aß precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits and exhibit robust neuroinflammation. In the present study, we investigated the effect of the anti-inflammatory drug minocycline on Aß accumulation, neuroinflammation, and behavioral deficits in Tg-SwDI mice. Twelve-month-old mice were treated with saline or minocycline by intraperitoneal injection every other day for a total of 4 weeks. During the final week of treatment, the mice were tested for impaired learning and memory. Brains were then harvested for biochemical and immunohistochemical analysis. Minocycline treatment did not alter the cerebral deposition of Aß or the restriction of fibrillar amyloid to the cerebral microvasculature. Similarly, minocycline-treated Tg-SwDI mice exhibited no change in the levels of total Aß, the ratios of Aß40 and Aß42, or the amounts of soluble, insoluble, or oligomeric Aß compared with the saline-treated control Tg-SwDI mice. In contrast, the numbers of activated microglia and levels of interleukin-6 were significantly reduced in minocycline-treated Tg-SwDI mice compared with saline-treated Tg-SwDI mice. In addition, there was a significant improvement in behavioral performance of the minocycline-treated Tg-SwDI mice. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Aß.

Key words: cerebral microvascular amyloid; neuroinflammation; cognitive impairment; microglia; transgenic mice; behavior

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Received Oct. 6, 2006; revised Jan. 29, 2006; accepted Feb. 11, 2007.

Correspondence should be addressed to Dr. William E. Van Nostrand, Department of Medicine, HSC T-15/083, Stony Brook University, Stony Brook, NY 11794-8153. Email: william.vannostrand{at}stonybrook.edu

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