Increased synaptic sprouting in response to estrogen via an apolipoprotein E-dependent mechanism: implications for Alzheimer's disease.
Estrogen replacement therapy appears to delay the onset of Alzheimer's disease (AD), but the mechanisms for this action are incompletely known. We show how the enhancement of synaptic sprouting by estradiol (E2) in response to an entorhinal cortex (EC) lesion model of AD may operate via an apolipoprotein E (apoE)-dependent mechanism. In wild-type (WT) mice, ovariectomy decreased commissural/associational sprouting to the inner molecular layer of the dentate gyrus, with synaptophysin (SYN) as a marker. E2 replacement returned SYN in the inner layer to levels of EC-lesioned, ovary-bearing controls and increased the area of compensatory synaptogenesis in the outer molecular layer. In EC-lesioned apoE-knock-out (KO) mice, however, E2 did not enhance sprouting. We also examined apoJ (clusterin) mRNA, which is implicated in AD by its presence in senile plaques, its transport of Abeta across the blood-brain barrier, and its induction by neurodegenerative lesioning. ApoJ mRNA levels were increased by E2 replacement in EC-lesioned WT mice but not in apoE-KO mice. These data suggest a mechanism for the protective effects of estrogens on AD and provide a link between two important risk factors in the etiology of AD, the apoE epsilon4 genotype and an estrogen-deficient state. This is also the first evidence that SYN, a presynaptic protein involved in neurotransmitter release, is regulated by E2 in the adult brain, and that apoE is necessary for the induction of apoJ mRNA by E2 in brain injury.
Stone
D J
DJ
Andrus Gerontology Center and the Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-0191, USA.
Rozovsky
I
I
Morgan
T E
TE
Anderson
C P
CP
Finch
C E
CE
D000544:Alzheimer Disease / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D051152:Clusterin; D015914:Estrogen Replacement Therapy; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013569:Synapses / Q000187:drug effects*; D016708:Synaptophysin / Q000032:analysis
D001057:Apolipoproteins E; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016708:Synaptophysin