Androgen regulation of beta-amyloid protein and the risk of Alzheimer's disease

Abstract

Advancing age is the most significant risk factor for the development of Alzheimer's disease (AD), however the age-related changes that underlie this effect remain unclear. In men, one normal consequence of aging is a robust decline in circulating and brain levels of the sex steroid hormone testosterone. Testosterone depletion leads to functional impairments and increased risk of disease in androgen-responsive tissues throughout the body, including brain. In this review we discuss the relationship between age-related testosterone depletion and the development of AD. Specifically, we focus on androgen regulation of beta-amyloid protein (Abeta), the accumulation of which is a key initiating factor in AD pathogenesis. Emerging data suggest that the regulatory actions of androgens on both Abeta and the development of AD support consideration of androgen therapy for the prevention and treatment of AD.

Figure 1

Androgens regulate accumulation of Aβ in the triple transgenic model of AD (3xTg-AD). Immunostaining with anti-Aβ antibodies in adult (age 7 mo) male mice shows absent Aβ immunoreactivity in subiculum of wild-type mice (A), but significant intracellular accumulation in 3xTg-AD mice (B). 3xTg-AD mice that were androgen depleted by gonadectomy (GDX) at age 3 mo show a robust increase in Aβ accumulation at age 7 mo (C), an effect prevented by DHT treatment beginning immediately after GDX (D).

Figure 2

Androgen regulation of Aβ may involve three general pathways. Aging decreases testosterone, which can reduce Aβ levels directly by androgen receptor (AR)-dependent regulation of the Aβ-catabolizing enzyme neprilysin (NEP) and indirectly by aromatization to 17β-estradiol, which has been shown to reduce amyloidogenic processing of the Aβ precursor protein (APP). Through regulation of the hypothalamic-pituitary-gonadal axis, age-related testosterone depletion also elevates LH levels, which have been associated with increased Aβ by an incompletely defined mechanism that may include the LH receptor (LHR)