抄録
Several epidemiological studies show that estrogen replacement therapy (ERT) protects against the development of Alzheimer's disease (AD) in postmenopausal women. ERT may slow AD progression by reducing the release of Aβ, the primary constituent of amyloid plaques and the major determinant of AD pathogenesis, into brain parenchyma. This Aβ burden is reversible with post-surgical estrogen replacement. In addition, a recent study demonstrates an inverse relationship between the levels of 17β-E2 and Aβ42, the more amyloidogenic Aβ variant, in the cerebrospinal fluid of female AD patients. Our recent study demonstrated that, like estrogen, testosterone increases the secretion of the nonamyloidogenic APP fragment and decreases the secretion of Aβ. This result raises the possibility that testosterone supplementation in elderly men may be protective in the treatment of AD.
Production of Aβ peptides from β-amyloid precursor protein (APP) requires sequential proteolytic cleavages by the β- and γ-secretases, mostly occurring in the trans-Golgi Network (TGN) where APP molecules predominantly reside. We recently demonstrated that estrogen may exert by regulating APP trafficking from the TGN and hence reduce the availability of APP for the secretase cleavages. These data suggest a novel mechanism through which estrogen exerts its anti-Aβ effects in estrogen-responsive tissues and illustrate how altering the kinetics of a protein's transport can influence its metabolic fate. It is our goal to identify regulatory factors that reduce Aβ generation and to elucidate potential therapeutic targets in AD. [Jpn J Physiol 54 Suppl:S61 (2004)]
