Neuroprotective mechanism conferred by 17beta-estradiol on the biochemical basis of Alzheimer's disease.
Estrogen (17beta-estradiol) plays key regulatory roles in a variety of physiological and biological processes. Several lines of evidence also support its role as a protective factor in Alzheimer's disease; however, the basis of this effect is unclear. Here we show that an early-onset Alzheimer's disease transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F) undergoing treatment with 17beta-estradiol show significantly lower levels of APP processing through beta-secretase and enhanced alpha-secretase processing resulting in marked reductions of APP-CTFbeta, Abeta42 and plaque burden, along with increased levels of the non-amyloidogenic sAPPalpha. Moreover, 17beta-estradiol resulted in elevated brain levels of transthyretin, which inhibits aggregation of Abeta into plaques; though the insulin-degrading enzyme, which breaks down Abeta, was significantly reduced. These results illustrate a multifaceted effect of 17beta-estradiol on the biochemical basis of Alzheimer's disease, through effects on APP processing, Abeta levels and factors that affect its clearance and aggregation. Overall, these results support the need for further long-term longitudinal studies to elucidate consequences of menopause as well as hormone therapy on Alzheimer's disease, and explore its potential as a therapeutic avenue for the disease.
Amtul
Z
Z
Department of Biochemistry, University of Western Ontario, London, ON, Canada. zamtul@uwo.ca
Wang
L
L
Westaway
D
D
Rozmahel
R F
RF
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000187:drug effects / Q000473:pathology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004967:Estrogens; D018696:Neuroprotective Agents; D004958:Estradiol; D053829:Amyloid Precursor Protein Secretases