Hormonal replacement therapy reduces b-amyloid toxicity : an alzheimer's disease treatment model.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease and the main cause of geriatric dementia. A key event in AD is the accumulation ofthe 1-42 amino acid fragment of ~-amyloid (A~I-42). Clinical studies indicate that both 17-~-estradiol and IGF-I (when used separately) improve cognition and can protect cells from AD. Both hormones decrease in plasma with age, more so in women where 17-~-estradiol circulation falls to about 1% of pre-menopausal levels. I wanted to determine if combinatorial hormone replacement therapies of steroid and peptide hormones would lead to a synergistic protective effect against AD compared to single hormone replacement therapy. Hippocampal hybridoma HT22 cells were exposed to A~I-42 or nontoxic controls (A~4o-10r 0.01% dimethylsulfoxide (DMSO)) and were additionally treated with different combinations and concentrations of hormones. After six days, survival ofHT22 cells was measured by MTT (3-(4, 5-dimethylthiazol-2-y)-2, 4diphenyltetrazolium bromide) assay and the results were expressed as percentage of the untreated control. A~I-42 significantly reduced cell survival (P <O.OOOL ANOVA, N=16) compared to A~40-1 or DMSO controls regardless ofIGF-I dose (0 11M to 111M), estradiol dose (0 flM-IO 11M) or any combination of the two hormones. IGF-I contributed to significantly higher HT22 cell survival (P <0.0001, ANOVA) for all combinations of peptides (API-42, AP40-J, and DMSO) and estradiol (0 flM to 10 flM). Estradiol did not contribute to any significant improvement of cell survival (P >0.05, ANOY A) and a higher dose was deleterious (P <0.004, ANOYA). No positive interaction between IOF-I and estradiol at any of the combinations of hormones was found for API-42, AP40-1 or DMSO treated cells (P >0.05, ANOYA). In conclusion, IOF-I is able to protect HT22 cells from API-42 toxicity while estrogen did little to protect the cultured neurons from Ap 1-42. The failure of estrogen to protect HT22 neurons from p-amyloid could be due to lack of astrocytes that appear to mediate estrogen's effect by producing IOF-I.