Increased Synaptic Sprouting in Response to Estrogen via an Apolipoprotein E-Dependent Mechanism: Implications for Alzheimer’s Disease

Abstract

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 (E 2 ) 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. E 2 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, E 2 did not enhance sprouting. We also examined apoJ (clusterin) mRNA, which is implicated in AD by its presence in senile plaques, its transport of A␤ across the blood-brain barrier, and its induction by neurodegenerative lesioning. ApoJ mRNA levels were increased by E 2 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 ⑀4 genotype and an estrogen-deficient state. This is also the first evidence that SYN, a presynaptic protein involved in neurotransmitter release, is regulated by E 2 in the adult brain, and that apoE is necessary for the induction of apoJ mRNA by E 2 in brain injury.

Apolipoprotein E4 Influences Amyloid Deposition But Not Cell Loss after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

“…These processes include A␤ oligomer formation, tangle formation, cell loss, and synaptic loss. Some in vivo studies have found that apoE influences aspects of brain function and plasticity after different forms of injury Sheng et al, 1998;Stone et al, 1998;Buttini et al, 1999;Genis et al, 2000;Sabo et al, 2000), including TBI (Chen et al, 1997), and it is possible that APOE influences the outcome after different forms of brain injury via more than one mechanism. Our data suggest that understanding the mechanism(s) by which TBI promotes APOE isoform-dependent amyloid deposition will lead to important insights into how accelerated A␤-related AD-like changes occur and potential ways to prevent it.…”

Low Doses of 17α-Estradiol and 17β-Estradiol Facilitate, Whereas Higher Doses of Estrone and 17α- and 17β-Estradiol Impair, Contextual Fear Conditioning in Adult Female Rats

“…Specifically, 17b-estradiol increases the number of spines and synapses in the CA1 field of the hippocampus (Woolley et al, 1990;Woolley and McEwen, 1992), and synaptophysin, a presynaptic protein that is a critical component of synaptic vesicle exocytosis, in the hippocampus (Murphy and Segal, 1996;Stone et al, 1998;Pozzo-Miller et al, 1999;Frick et al, 2002). Importantly, the increase in synaptophysin expression in the whole hippocampus is associated with enhanced spatial reference memory (Frick et al, 2002).…”

The effect of hormone therapy on olfactory sensitivity is dependent on apolipoprotein E genotype

“…This effect has been demonstrated in brain glial cells as well when high levels of endogenous 17β-estradiol are present (Stone et al,1997). In addition, Stone et al (1998) demonstrated that, in the dentate gyrus, estradiol replacement restored decreased levels of synaptic sprouting in an AD mouse model that was estrogen deficient due to ovariectomy. However, this restorative effect of exogenous estradiol on decreased sprouting was absent in ApoE-knock-out mice (Stone et al, 1998).…”

“…In addition, Stone et al (1998) demonstrated that, in the dentate gyrus, estradiol replacement restored decreased levels of synaptic sprouting in an AD mouse model that was estrogen deficient due to ovariectomy. However, this restorative effect of exogenous estradiol on decreased sprouting was absent in ApoE-knock-out mice (Stone et al, 1998). Further demonstrating the interaction between estrogen and ApoE is the finding by Nathan and colleagues (2004) that estradiol increased neuron growth in cultured mouse cortical neurons in neurons expressing the ApoE ε2 or ε3 allele; however, estradiol had no effect on neurons expressing the ε4 allele.…”