Amyloid β Precursor Protein Regulates Male Sexual Behavior

Abstract

Sexual behavior is variable between individuals, ranging from celibacy to sexual addictions. Within normal populations of individual men, ranging from young to middle aged, testosterone levels do not correlate with libido. To study the genetic mechanisms that contribute to individual differences in male sexual behavior, we used hybrid B6D2F1 male mice, which are a cross between two common inbred strains (C57BL/6J and DBA/2J). Unlike most laboratory rodent species in which male sexual behavior is highly dependent upon gonadal steroids, sexual behavior in a large proportion of these hybrid male mice after castration is independent of gonadal steroid hormones and their receptors; thus, we have the ability to discover novel genes involved in this behavior. Gene expression arrays, validation of gene candidates, and transgenic mice that overexpress one of the genes of interest were used to reveal genes involved in maintenance of male sexual behavior. Several genes related to neuroprotection and neurodegeneration were differentially expressed in the hypothalamus of males that continued to mate after castration. Male mice overexpressing the human form of one of these candidate genes, amyloid ␤ precursor protein (APP), displayed enhanced sexual behavior before castration and maintained sexual activity for a longer duration after castration compared with controls. Our results reveal a novel and unexpected relationship between APP and male sexual behavior. We speculate that declining APP during normal aging in males may contribute to the loss of sexual function.

Inheritance of steroid-independent male sexual behavior in male offspring of B6D2F1 mice

“…Because previous studies determined that increased APP, tau, and synaptophysin expression levels in the MPOA of B6D2F1 hybrid male mice were associated with steroid-independent male sexual behavior, we analyzed levels of these proteins in not only the B6D2F1 maters and non-maters, but their male offspring as well (Bharadwaj et al, 2013; Park et al, 2010). In concordance with previously reported results, Western blots of APP, tau, and synaptophysin from MPOA tissues showed that all three proteins were significantly higher in B6D2F1 maters relative to those in B6D2F1 non-maters [(p<0.05 for all comparisons; Figure 2A–C; APP: F-value ( 1,8 ) = 7.034, p < 0.05, η 2 =0.88; tau: F-value ( 1,8 ) = 8.476, p < 0.05, η 2 =0.94; synaptophysin: F-value ( 1,8 ) = 5.764, p < 0.05, η 2 =0.72].…”

“…We further investigated two genes in particular, amyloid beta (A4) precursor protein ( App , located on chromosome 16 in the mouse) and microtubule associated protein tau ( Mapt , located on chromosome 11 in the mouse), which are normally associated with Alzheimer’s Disease. Expression of these genes and proteins were significantly higher in maters relative to the non-maters (Park et al, 2010). Furthermore, transgenic male mice that overexpressed either APP or tau, the two proteins products of App and Mapt , respectively, displayed enhanced sexual behavior after orchidectomy compared to control wildtype littermates, demonstrating that the relationship of APP and tau with male sexual behavior were both beyond correlational (Bharadwaj et al, 2013; Park et al, 2010).…”

“…Expression of these genes and proteins were significantly higher in maters relative to the non-maters (Park et al, 2010). Furthermore, transgenic male mice that overexpressed either APP or tau, the two proteins products of App and Mapt , respectively, displayed enhanced sexual behavior after orchidectomy compared to control wildtype littermates, demonstrating that the relationship of APP and tau with male sexual behavior were both beyond correlational (Bharadwaj et al, 2013; Park et al, 2010). Because the normal function of both genes have been associated with synaptic plasticity, this led to an investigation that revealed that relative to B6D2F1 non-maters, the maters exhibited higher levels of synaptophysin, a protein generally enriched in synapses and associated with synaptic connectivity ( synaptophysin gene located on the X chromosome) (Bharadwaj et al, 2013).…”

“…A gene expression analyses of the MPOA between B6D2F1 hybrid maters and non-maters revealed over 500 differentially expressed genes (Park et al, 2010). We further investigated two genes in particular, amyloid beta (A4) precursor protein ( App , located on chromosome 16 in the mouse) and microtubule associated protein tau ( Mapt , located on chromosome 11 in the mouse), which are normally associated with Alzheimer’s Disease.…”

Genetic and epigenetic underpinnings of sex differences in the brain and in neurological and psychiatric disease susceptibility

“…APP promoter methylation is higher in females and differentially regulated by sex steroids in mouse cerebral cortex (Mani and Thakur, 2006). Also, APP has been linked to male sexual behavior (Park et al, 2010b). In contrast to AD, men are about 1.5 times more likely to develop PD than women.…”