AR, apoE, and cognitive function

Abstract

Reduced androgen levels in aged men and women might be risk factors for age-related cognitive decline and Alzheimer's disease (AD). Ongoing clinical trials are designed to evaluate the potential benefit of estrogen in women and of testosterone in men. In this review, we discuss the potential beneficial effects of androgens and androgen receptors (ARs) in males and females. In addition, we discuss the hypothesis that AR interacts with apolipoprotein (apoE)4, encoded by ε4 and a risk factor for age-related cognitive decline and AD, and the potential consequences of this interaction.

Introduction

Increasing age and female sex are risk factors for developing mild cognitive impairments (MCI) and Alzheimer's disease (AD) (Farrer et al., 1997, Fratiglioni et al., 1997, Gao et al., 1998; for review (Raber et al., 2004)). Therefore, evaluating risk factors and therapeutic strategies for these age-related impairments become increasingly important. We will discuss the potential roles of androgens and androgen receptors (ARs) in cognitive function in humans and mice and potential interactions of androgens and ARs with apolipoprotein E.

There are sex differences in spatial learning and memory in humans (Berger-Sweeney et al., 1995, Reinisch et al., 1991, Roof and Havens, 1992) and rodents (Beatty, 1979, van Haaren et al., 1990). Spatial learning and memory is relevant, as it is impaired in Alzheimer's disease (AD). Some, but not all (Bucci et al., 1995), studies of spatial learning and memory in rodents have shown that males learn more quickly than females and exhibit superior performance in a variety of mazes (Bucci et al., 1995, Einon, 1980, Frye, 1995, Joseph and Gallagher, 1980, Luine et al., 1986, McEwen, 1988, McNemar and Stone, 1932, Means and Dent, 1991, Roof, 1993). Spatial learning and memory have been attributed to the hippocampus (Kesner et al., 1993, Olton et al., 1978) and sex differences in hippocampal structure may contribute to sex differences in spatial learning and memory (McEwen et al., 1997). Different strategies used by males and females to solve spatial tasks may contribute to these sex differences. Females tend to rely more on local cues and landmarks, while males rely more on the spatial relationship between fixed points. Rodent lesion and pharmacological studies support that females may be more susceptible to spatial memory impairments than males (Hörtnagl et al., 1993, Kolb and Cioe, 1996).

Sex steroids, which cause sex differences in brain organization (organizational effect) (Beatty, 1979) and in behaviors in adulthood (activational effect) (Joseph et al., 1978), might contribute to sex differences in spatial learning and memory (Joseph et al., 1978).

Androgens might contribute to the sex differences in spatial learning and memory. In adulthood, testosterone enhances spatial memory (Alexander et al., 1994, Flood and Roberts, 1988, Ishunina et al., 2002, Janowsky et al., 1994, Raber et al., 2002, Vazquez-Pereyra et al., 1995) and androgens also enhance both short-term and long-term emotional learning and memory (Vazquez-Pereyra et al., 1995). In addition, post-training administration of androgens to ovariectomized rats enhanced spatial and emotional learning and memory (Frye and Lacey, 2001). However, in some studies androgens impaired spatial learning and memory (Galea et al., 1995, Gouchie and Kimura, 1991, Goudsmit et al., 1990, Hampson, 1995, Naghdi et al., 2001).

Androgens such as dihydrotestosterone (DHT) initiate many of their effects by binding to AR (Barley et al., 1975). The human AR gene contains 8 exons encoding a 110 kDa member of the nuclear receptor superfamily (Simental et al., 1992). The first exon encodes the N-terminal domain containing the major transactivation function (AF-1), which interacts with the glutamine-rich region of steroid receptor coactivator-1 (SRC-1) (Robyr et al., 2000). SRC-1 in turn can interact with the global activator CBP/p300, which can directly interact with ARs and together with SRC-1 synergistically induce AR transactivation (McKenna et al., 1999). The second and third exons encode the DNA binding domain (DBD), which enable ARs to bind the regulatory part of target genes (Umesono and Evans, 1989). Exons 4–8 encode the ligand binding domain (LBD) and a minor transactivation function (AF-2). AF-2 also interacts with SRC-1 (Umesono and Evans, 1989). The activity of SRC-1 is regulated by phosphorylation by mitogen-activated protein kinase (MAPK), which is stimulated by androgens. In the absence of hormone, the LBD of AR prevents the transactivation of AF-1 and the required three-dimensional structures for SRC-1 interaction at AF-2. Hormone binding enables AF-1 and AF-2 to associate with a multi-subunit complex of coactivator proteins. This complex is proposed to associate additional proteins required for interaction of AR to RNA polymerase II. AR can also be activated in a ligand-independent fashion. For example, growth factors and Interleukin-6 (IL-6) activate ARs in the absence of androgen. Point mutations at different sites in exons 2–8 have been reported for partial and complete forms of androgen insensitivity. In human prostate cancer cells, the ligand-independent activation of ARs by IL-6 involves phosphorylation of SRC-1 by MAPK (Ueda et al., 2002). However, it should be emphasized that SRC-1 phosphorylation requires the presence of IL-6 and by itself is not sufficient for ligand-independent transactivation of ARs (Ueda et al., 2002).

AR not bound to hormone is localized in the cytoplasm as a complex with heat-shock proteins and immunophilins. When androgens bind, AR changes its conformation, dissociates from the complex, forms homodimers, and unmasks its nuclear localization signal. This signal can then bind importins, which transport the hormone-bound AR into the nucleus. ARs can modulate gene transcription by binding to specific androgen response elements in the DNA, but are also able to trans-activate and trans-repress without directly interacting with specific DNA elements. The calcium-binding protein calreticulin is able to dissociate AR from the DNA by competing for the DBD of the AR and may export AR back to the cytoplasm. Hormone-dissociated AR moves back to the cytoplasm ready for another nuclear translocation. In addition to nuclear receptor pathways (genomic effects), androgens might also mediate their effects by mechanisms not involving nuclear receptors (nongenomic effects).

Increasing evidence supports an important role for androgens and ARs in hippocampal function. The levels of AR mRNA and AR binding in the hypothalamus and hippocampus of male rats are similar (Burgess and Handa, 1993, Kerr et al., 1995). In addition, androgens increase spine-synapse density in the CA1 of ovariectomized female rodents (Leranth et al., 2004, Woolley et al., 1990). While there are no absolute sexual differences in AR mRNA (Simerly et al., 1990) and AR binding (Handa et al., 1986) in adult rat brain, differences in circulating androgen levels could modulate AR function in a sex-dependent fashion. Neonatal castration of males or prenatal treatment of DHT to females reverses the sex difference in CA3 pyramidal cell layer volume and neuronal cells soma sizes, which correlates with water maze performance in adulthood (Isgor and Sengelaub, 1998). Circulating androgens may also be important in sustaining neuron synapses in CA3 later in life. The decline in synaptic density in CA3 neurons in aged male rats is associated with age-related deficits in spatial ability (Geinisman et al., 1995). Further, DHT selectively modulates the induction of the mRNA for the cellular immediate early gene c-fos in the CA1 region of the hippocampus following exposure to a novel open field for 20min (Kerr et al., 1996). Finally, DHT attenuates the binding of the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 in CA1 (Kus et al., 1995) and modulates NMDA-mediated depolarization in CA1 pyramidal cells (Pouliot et al., 1996).