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The Journal of Neuroscience, May 7, 2008, 28(19):5007-5017; doi:10.1523/JNEUROSCI.0590-08.2008

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Neurobiology of Disease
Enkephalin Elevations Contribute to Neuronal and Behavioral Impairments in a Transgenic Mouse Model of Alzheimer's Disease

William J. Meilandt,^1,2 Gui-Qiu Yu,¹ Jeannie Chin,^1,2 Erik D. Roberson,^1,2 Jorge J. Palop,^1,2 Tiffany Wu,¹ Kimberly Scearce-Levie,^1,2 and Lennart Mucke^1,2

¹Gladstone Institute of Neurological Disease and ²Department of Neurology, University of California, San Francisco, California 94158

Correspondence should be addressed to Dr. Lennart Mucke, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: lmucke{at}gladstone.ucsf.edu

The enkephalin signaling pathway regulates various neural functions and can be altered by neurodegenerative disorders. In Alzheimer's disease (AD), elevated enkephalin levels may reflect compensatory processes or contribute to cognitive impairments. To differentiate between these possibilities, we studied transgenic mice that express human amyloid precursor protein (hAPP) and amyloid-β (Aβ) peptides in neurons and exhibit key aspects of AD. Met-enkephalin levels in neuronal projections from the entorhinal cortex and dentate gyrus (brain regions important for memory that are affected in early stages of AD) were increased in hAPP mice, as were preproenkephalin mRNA levels. Genetic manipulations that exacerbate or prevent excitotoxicity also exacerbated or prevented the enkephalin alterations. In human AD brains, enkephalin levels in the dentate gyrus were also increased. In hAPP mice, enkephalin elevations correlated with the extent of Aβ-dependent neuronal and behavioral alterations, and memory deficits were reduced by irreversible blockade of µ-opioid receptors with the antagonist β-funaltrexamine. We conclude that enkephalin elevations may contribute to cognitive impairments in hAPP mice and possibly in humans with AD. The therapeutic potential of reducing enkephalin production or signaling merits further exploration.

Key words: enkephalin; mu-opioid receptor; amyloid; dentate gyrus; entorhinal cortex; spatial memory

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Received Oct. 8, 2007; revised March 27, 2008; accepted March 31, 2008.

Correspondence should be addressed to Dr. Lennart Mucke, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: lmucke{at}gladstone.ucsf.edu

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