INCREASED SYNAPTIC SPROUTING IN RESPONSE TO ESTROGEN VIA AN APOLIPOPROTEIN E-DEPENDENT MECHANISM - IMPLICATIONS FOR ALZHEIMERS-DISEASE

Estrogen replacement therapy appears to delay the onset of Alzheimer's disease (AD), but the mechanisms for this action are incompletely kno wn. We show how the enhancement of synaptic sprouting by estradiol (E- 2) in response to an entorhinal cortex (EC) lesion model of AD may ope rate via an apolipoprotein E (apoE)-dependent mechanism. In wild-type (WT) mice, ovariectomy decreased commissural/associational sprouting t o the inner molecular layer of the dentate gyrus, with synaptophysin ( SYN) as a marker. E-2 replacement returned SYN in the inner layer to l evels of EC-lesioned, ovary-bearing controls and increased the area of compensatory synaptogenesis in the outer molecular layer. In EC-lesio ned apoE-knock-out (KO) mice, however, E-2 did not enhance sprouting. We also examined apoJ (clusterin) mRNA, which is implicated in AD by i ts presence in senile plaques, its transport of A beta across the bloo d-brain barrier, and its induction by neurodegenerative lesioning. Apo J 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 prote ctive effects of estrogens on AD and provide a link between two import ant risk factors in the etiology of AD, the apoE epsilon 4 genotype an d an estrogen-deficient state. This is also the first evidence that SY N, a presynaptic protein involved in neurotransmitter release, is regu lated by E-2 in the adult brain, and that apoE is necessary for the in duction of apoJ mRNA by E-2 in brain injury.