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The Journal of Neuroscience, June 15, 2002, 22(12):5204-5209
Androgens Protect against Apolipoprotein E4-Induced
Cognitive Deficits
Jacob
Raber1, 2,
Gerold
Bongers1,
Anthony
LeFevour1,
Manuel
Buttini1, and
Lennart
Mucke1, 2
1 Gladstone Institute of Neurological Disease and
2 Department of Neurology, University of California, San
Francisco, California 94141
Compared with apolipoprotein (apo) E2 and E3, apoE4 increases the
risk of Alzheimer's disease (AD), but it remains unknown how apoE4
affects neuronal function. ApoE4 interacts with female gender, further
increasing the risk of AD and decreasing treatment response. Female
mice are also more susceptible to apoE4-induced impairments of spatial
learning and memory than male mice. To assess the role of sex steroids
in this process, we studied mice deficient in mouse apoE
(Apoe /) and expressing
human apoE4 or apoE3 in the brain at comparable levels. Even brief
periods of androgen treatment improved the memory deficits of female
apoE4 mice. Female apoE3 mice had no memory deficits and did not
benefit from the treatment. ApoE4 male mice, which performed normally
in a water-maze test at baseline, developed prominent deficits in
spatial learning and memory after blockade of androgen receptors (ARs),
whereas apoE3 male mice did not. Untreated apoE4 mice had significantly
lower cytosolic AR levels in the neocortex than wild-type,
Apoe/, and apoE3 mice. Improved
memory in androgen-treated female apoE4 mice was associated with
increased cytosolic AR levels. Our findings suggest that apoE4
contributes to cognitive decline by reducing AR levels in the brain,
and that stimulating AR-dependent pathways can reverse apoE4-induced
cognitive deficits.
Key words:
apoE; spatial learning and memory; novel object
recognition; testosterone; dihydrotestosterone; androgen receptor; hydroxyflutamide
Copyright © 2002 Society for Neuroscience 0270-6474/02/22125204-06$05.00/0
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