Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain.
OBJECTIVE
To test whether female gonadal hormone status and estrogen modulate the metabolism of Abeta peptides in vivo.


BACKGROUND
AD is a neurodegenerative disorder characterized by accumulation of aggregated forms of the 40- and 42-amino acid Abeta peptides (Abeta40 and Abeta42). Estrogen replacement therapy in postmenopausal women is associated with decreased risk for AD or delay in disease onset or both. The mechanism by which estrogen exerts this neuroprotective effect is elusive. 17beta-estradiol (E2) was shown to reduce the release of Abeta peptides by primary neuronal cultures of murine and human origin.


METHODS
For this purpose, four experimental sets of guinea pigs were used: intact animals, ovariectomized animals (ovx), and ovariectomized animals that received E2 at two different doses (ovx+low-dose E2 and ovx+high-dose E2). Brain Abeta40 and Abeta42 levels were assessed using Abeta40 and Abeta42-specific ELISA assays.


RESULTS
Prolonged ovariectomy resulted in uterine atrophy and decreased serum E2 levels and was associated with a pronounced increase in brain Abeta levels. Total brain Abeta in the ovx animals was increased by 1. 5-fold on average as compared to intact controls. E2 treatment of ovariectomized animals led to uterine hypertrophy and a dose-dependent increase in serum E2 levels. In addition, both doses of E2 significantly reversed the ovariectomy-induced increase in brain Abeta levels. The high-dose E2 treatment did not lead to a further decrease in brain Abeta beyond that observed with the low-dose E2 treatment.


CONCLUSIONS
Our results infer that cessation of ovarian estrogen production in postmenopausal women might facilitate Abeta deposition by increasing the local concentrations of Abeta40 and Abeta42 peptides in brain. In addition, our finding that E2 treatment is associated with diminution of brain Abeta levels suggests that modulation of Abeta metabolism may be one of the ways by which estrogen replacement therapy prevents or delays the onset of AD or both in postmenopausal women.
Petanceska
S S
SS
New York University at Nathan Kline Institute, Orangeburg, NY 10962, USA.
Nagy
V
V
Frail
D
D
Gandy
S
S
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010446:Peptide Fragments / Q000378:metabolism; D014599:Uterus / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D004958:Estradiol