Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
    • Special Collections
  • EDITORIAL BOARD
    • Editorial Board
    • ECR Advisory Board
    • Journal Staff
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
    • Accessibility
  • SUBSCRIBE

User menu

  • Log out
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log out
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
    • Special Collections
  • EDITORIAL BOARD
    • Editorial Board
    • ECR Advisory Board
    • Journal Staff
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
    • Accessibility
  • SUBSCRIBE
PreviousNext
Featured ArticleArticles, Behavioral/Systems/Cognitive

Amyloid β Precursor Protein Regulates Male Sexual Behavior

Jin Ho Park, Paul J. Bonthius, Houng-Wei Tsai, Stefan Bekiranov and Emilie F. Rissman
Journal of Neuroscience 28 July 2010, 30 (30) 9967-9972; https://doi.org/10.1523/JNEUROSCI.1988-10.2010
Jin Ho Park
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul J. Bonthius
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Houng-Wei Tsai
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefan Bekiranov
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Emilie F. Rissman
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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 β 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.

Introduction

One of the most highly conserved and evolutionarily important behaviors is copulation. In most laboratory rodents male sexual behavior (MSB) is dependent upon gonadal hormones and their corresponding steroid receptors. This association between mating and gonadal steroids is a product of evolution since small short-lived mammals in the temperate zone restrict their mating to discreet times of the year (Bronson, 1989). Thus coordination of sperm production and mating behaviors is critical. In other vertebrates, particularly larger mammals, the role of gonadal steroids in MSB is less predictable and highly variable. Humans are an excellent example of a species in which individual differences in sexual behavior are prominent. Among normal men, testosterone levels in plasma do not correlate with reported sexual activity (Bagatell et al., 1994). Even castration or anti-androgen drug therapies produce wide and unpredictable variations in sexual activity ranging from no decline to a gradual waning in sexual activity (Phoenix et al., 1973; Micheal and Wilson, 1974).

One model organism for examining the genetics underlying these differences in behavior is the B6D2F1 hybrid male mice produced by crossing two common mouse strains, C57BL/6J and DBA/2J (McGill and Manning, 1976; Clemens et al., 1988). Approximately 30% of all B6D2F1 males retain the ability to display ejaculatory reflexes for as many as 25 weeks after castration (herein after referred to as maters). Thus within populations of these hybrids there is both behavioral and genetic diversity. After castration, maters and non-maters do not differ in concentrations of plasma testosterone (T), hypothalamic nuclear estrogen receptors or neural aromatase activity (Clemens et al., 1988; Sinchak et al., 1996). Blockade of androgen or estrogen receptors or aromatase enzyme which catalyzes the conversion of androgens to estrogens do not extinguish the expression of sexual behavior in maters (Park et al., 2009). To investigate the genetic bases for male sexual behavior gene expression analyses were conducted using tissue from brain regions essential for male copulatory behavior, including the medial preoptic nucleus (mPOA) and bed nucleus of the stria terminalis (BNST).

One of the top candidate genes identified from the gene expression analyses was amyloid β precursor protein (APP). APP is normally involved in cell survival and neuroprotection; however, when APP processing is altered, an increase in Aβ42 and N-APP occurs which impairs synaptic plasticity and induces aberrant neuronal and axonal degeneration (for review, see Kim and Tsai, 2009). Aberrant trafficking of APP may play a role in the pathogenesis of Alzheimer's disease (for review, see Selkoe, 1999; Sinha and Lieberburg, 1999). Relative expression of APP was upregulated in the maters when compared with the non-maters. To test the hypothesis that increased APP would enhance male sexual behavior, transgenic mice that overexpress human APP were examined.

Materials and Methods

Animals.

Male B6D2F1 hybrid mice (Mus musculus) were produced in the Jordan Hall Vivarium at the University of Virginia by crossing C57BL/6J females with DBA/2J males. Three different cohorts of male hybrid mice were used for the experiments. One cohort (n = 35) was used for the microarray study, another cohort (n = 40) for the quantitative reverse transcription (qRT)-PCR, and a third for the Western blots (n = 48). Hybrid B6D2F1 male mice were weaned at 20–21 d of age, single-sex group housed until the beginning of each of the experiments (between 50 and 80 d of age), and individually housed afterward for the rest of the experiments. All animals were maintained on a 12 h light/dark cycle (lights off at 12:00 P.M. EST). All of the mice received food (Harlan Diet 8604) and water ad libitum in the University of Virginia Animal Care Facility.

C57BL/6J females were used as stimulus females for MSB testing. Females were ovariectomized and injected subcutaneously with 0.5 μg of estradiol (dissolved in sesame oil) 48 h before testing. Three to 5 h before testing, stimulus females were injected subcutaneously with 0.83 μg of progesterone. The females were group-housed in the same colony room as the experimental males.

APP transgenic mice (B6.129S2-Tg(APP)8.9Btla/J; Jackson Laboratory; stock #5301; n = 10) were developed by transfecting a 650 kb YAC transgene containing entire human APP gene (and ∼350 kb flanking sequence) into 129S2/SvPas-derived D3 embryonic stem cells (Lamb et al., 1993). Founder animals were backcrossed to C57BL/6J for 11 generations. These mice express all mRNA and protein isoforms of the wild-type human amyloid β (A4) precursor protein, APP, and the expression pattern of the various protein isoforms of human APP mimics endogenous mouse gene expression patterns. There is a ∼70% increase of total APP levels in brain extracts of the APP transgenic mice when compared with controls (Lamb et al., 1993). C57BL/6J males from our colony (n = 10) were used as controls. All animal procedures were conducted in accordance with our animal protocol, approved by the University of Virginia Committee on Animal Care and Use.

Behavioral testing.

MSB was tested under dim red lights during the dark phase of a light/dark cycle (Wersinger et al., 1997). All males were habituated 1 h before the introduction of the stimulus female in an 18 × 40 × 11 cm clear Plexiglas testing cage containing the male's home cage bedding. Tests began with the introduction of a hormone-treated stimulus female. Once the male mounted, the test continued to a criterion of a successful ejaculatory reflex or for 120 min, whichever occurred first. If the stimulus female became unreceptive during testing she was replaced with a receptive female.

All tests were videotaped and scored by an observer blind to the classification of the individuals. During each behavioral test, the behavioral components recorded were as follows: mount latency (ML; time from the introduction of a receptive female to the first mount), intromission latency (IL; time from the introduction of a receptive female to the first intromission), and ejaculation latency (EL; interval between the first intromission and ejaculation).

All males received sexual experience before castration. Males that continued to copulate after castration were considered to be “maters” if they demonstrated the ejaculation reflex on at least three of the last four behavioral tests, including the last test. Males used in the gene expression study were tested between weeks 22 and 28 postcastration, for the qRT-PCR experiment testing was performed between weeks 14 and 20 postcastration and males used for protein studies were tested on weeks 16–22 postcastration. APP transgenic mice and controls had 4 weekly MSB tests before castration and were retested for 12 weeks after castration.

Gene expression microarray.

Brains were rapidly dissected and frozen in dry ice and stored at −80°C. Brains were cut into 120-μm-thick coronal sections with a Bright cryostat. Based on the mouse brain atlas (Franklin and Paxinos, 1997), the brain areas containing the mPOA and BNST were dissected bilaterally from ∼8 single sections. Samples were homogenized at room temperature in QIAzol Lysis Reagent (Qiagen) and stored at −80°C until ready to be processed for RNA isolation. Qiagen kits were used to collect total RNA from brain areas containing both the mPOA and BNST from maters (n = 5) and non-maters (n = 5). Sufficiently high quality RNA was generated from each individual animal; thus providing five biological replicates for both groups.

The University of Virginia Biomolecular Facility (BMF) hybridized the mRNA samples to Affymetrix GeneChip Mouse Genome 430 2.0 Arrays that contains probe sets that monitor >39,000 transcripts. The BMF performed a number of quality control checks on the samples including the purity and concentration of the RNA. A number of quality control analyses were performed on the array data including intensity histogram plots, calculation of background levels, and fraction of probes sets detecting RNA. Normalized unscaled SE (NUSE) and relative log expression (RLE) plots, which are sensitive indicators of hybridization quality (Gentleman et al., 2005) were generated. The data were further checked for reproducibility by generating MvA plots which are pairwise scatter plots of M = difference of log intensities (y-axis) versus A = average log intensities (x-axis) for all replicates. All replicates compared well to each other; therefore all 10 arrays were included in the analysis. A principle components analysis also revealed that the maters and non-maters were well separated from each other, supporting the fact that the data were reproducible within each group and there was a significant change in global gene expression patterns when comparing maters and non-maters (supplemental Fig. S1, available at www.jneurosci.org as supplemental material).

Differentially expressed genes were identified by first quantile normalizing all arrays together (Bolstad et al., 2003) and then estimating relative log2 RNA abundance using the GCRMA (Wu et al., 2004) package in the Bioconductor software suite (Gentleman et al., 2005). Modified t tests on the log2 expression estimates using the limma package were performed (Smyth, 2004). The false discovery rate (FDR) (Benjamini and Hochberg, 1995; Benjamini and Yekutieli, 2001; Smyth, 2004) for each gene was estimated (i.e., the estimated rate of false-positives divided by the total positives derived from the t test p-values) to correct for the fact that ∼40,000 statistical tests were performed. A list of differentially expressed genes was derived by applying an FDR cutoff of 5%.

Quantitative RT-PCR.

Total RNA was isolated from mouse brain tissues using RNeasy Lipid Tissue Mini kit (Qiagen) as described by the manufacturer's protocol. The quantity (A 260) and quality (A 260/A 280) of RNA were determined (Bio-Rad SmartSpec Plus spectrophotometer). The cDNA templates were prepared using SuperScript Reverse Transcriptase (Invitrogen). The reverse transcription reaction consisting of 1 μg of total RNA, 500 ng of oligo (dT)12–18, 500 μm each dNTP, 10 mm DTT, 40 U of RNaseOUT RNase inhibitor, and 200 U of SuperScript RT was incubated at 37°C for 1 h and then heat-inactivated at 70°C for 15 min.

Real-time PCR was performed using ABI Prism 7300 Real-Time PCR System with Sequence Detection Software version 1.2.3 (Applied Biosystems). Separate β-actin endogenous control reactions were used to normalize RNA input. Oligonucleotide primers were designed using Primer Express version 2.0 and synthesized by Invitrogen (supplemental Table S3, available at www.jneurosci.org as supplemental material). The real-time PCR conditions were 95°C for 3 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. After the last PCR cycle, a dissociation melting curve stage was run according to software protocol. Target and endogenous control genes were measured in triplicate for each cDNA sample during each real-time run to avoid intersample variance. For each RNA sample a no-reverse transcriptase reaction was run in parallel to cDNA synthesis, and measured by qRT-PCR to control for contamination and genomic amplification. Each qRT-PCR was verified for a single PCR product of expected size with the disassociation melting curve stage, and some samples were checked with gel electrophoresis.

Normalization and quantifications of the genes of interest, and β-actin mRNA were performed with the comparative cycle thresholds (C T) method as described in the ABIPRISM7700 sequence detection system user bulletin (#2). Validation experiments were conducted to test for equally efficient target and endogenous control gene amplification as described in the user bulletin. All of the primers were at between 90 and 110% efficient for all amplifications.

Western blot analysis.

Maters (n = 10), non-maters (n = 6) and sexually experienced gonad intact (n = 6) hybrid mice were killed, and the mPOA and BNST were collected from each. Males were tested biweekly for sexual behavior between 10 and 20 weeks after castration; those that ejaculated on at least 5 of the 6 tests, including the last test, were considered maters and those that did not ejaculate on any of the tests were non-maters.

For protein extraction, brain tissues were thawed and homogenized in cold RIPA buffer (0.05 m Tris, 0.9% NaCl, 5 mm EDTA, pH = 7.4) with a protease inhibitor (Sigma). Tissue was homogenized, centrifuged and total protein concentrations were determined by BCA (bicinchoninic acid) Protein Assays (Pierce Chemical Co.). Samples were subjected to electrophoresis on 14% polyacrylamide-SDS gels and transferred to nitrocellulose. Membranes were blocked for 1 h then rinsed and incubated with APP antibodies (Millipore) overnight at 4°C. After rinsing, blots were incubated for 1 h in a horseradish peroxidase (HRP)-conjugated sheep anti-mouse IgG secondary antibody (1:10,000; Jackson Laboratory), followed by detection on x-ray film (Kodak X-OMAT) with SuperSignal West Pico Chemiluminescent Substrate (Pierce Chemical Co.). Later, blots were reprobed with antibody against β-actin (1:50,000; Sigma-Aldrich Corp.), and after rinsing, the blots were incubated for 1 h in an HRP-conjugated sheep anti-mouse IgG secondary antibody (1:10,000; Jackson Laboratory) followed by chemiluminescent detection. The intensities of each of the candidate proteins and β-actin were measured and analyzed by densitometry with ImageQuant (Molecular Dynamics). Levels of each of the candidates were normalized to those of β-actin in each sample and a standard which was run on every gel. The standard used to normalize between blots was the protein concentration of the frontal cortex of a randomly selected hybrid mouse.

Statistical analysis.

Chi-square tests were used to compare differences in the proportion of males displaying copulatory behavior between groups. Repeated ANOVAs were used to analyze the number of mounts and intromissions, as well as mount, intromission and ejaculation latencies of all mice. One-way ANOVAs were used to analyze mRNA levels and protein levels between groups. Post hoc comparisons were conducted using the Fisher Protected Least Significant Difference test where appropriate. Survival analyses were performed using the Mantel-Cox log-rank test to generate Kaplan-Meier curves which showed the percentage of mice displaying MSB at a specific time point during a behavioral test. Any test in which an animal never mounted was a censored data point of 7200 s indicating that the animal did not mount for at least the first 7200 s of the test. Any test in which an animal did not mount was dropped from the dataset for latency to intromit and ejaculate. The latency to intromit in any test in which an animal mounted but did not intromit was a censored data point calculated as 7200 s minus the latency to mount, and the test was dropped from the dataset for latency to ejaculate only. The latency to ejaculate in any test in which an animal intromitted but did not ejaculate, was a censored data point calculated as 7200 s minus latency to intromit starting from when the female was introduced. Observed differences were considered significant if p < 0.05. Statistical tests were run using the Statview program (Statview 5; SAS Institute).

Results

Five biological replicates for both groups were processed by Affymetrix gene expression arrays. Brain is a very complex tissue with diverse cell types and mRNA populations so it is important to apply rigorous statistical analysis of significance. A total of 532 differentially expressed genes were found after applying a 5% false discovery rate cutoff (Benjamini and Hochberg, 1995; Benjamini and Yekutieli, 2001; Smyth, 2004). Of these, expression of 267 genes was downregulated and expression of 265 genes was upregulated in maters relative to non-maters (supplemental Table S1, available at www.jneurosci.org as supplemental material). This list of candidates and their corresponding fold changes were entered into Pathway Express (Khatri and Drăghici, 2005). Seven of the 12 most impacted pathways were neurophysiological with 6 involved in neurodegenerative disease (Table 1). The list of candidate genes was further narrowed by genotype data from recombinant inbred mouse lines generated from the B6D2F1 hybrid mice (labeled BXD1–100). Previously (Coquelin, 1991) two recombinant lines of B6D2F1 mice that displayed mating after castration and four lines that ceased mating after surgery were identified. A total of 152 alleles at specific loci were identical among the two mater strains but differed from those in the four non-mating strains (supplemental Table S2, available at www.jneurosci.org as supplemental material). Cross referencing the unique genes from the BXD recombinant mice that mated with the genes from our microarray analysis, two additional genes were identified. The six genes that are strong candidates which may play an important role in mediating persistent copulation in long-term castrated B6D2F1 hybrid mice are listed in Table 2.

View this table:
  • View inline
  • View popup
Table 1.

The top 12 biological pathways impacted by changes in gene expression between maters and controls calculated using Pathway Express

View this table:
  • View inline
  • View popup
Table 2.

Candidate genes identified that may mediate persistent copulation in long-term orchidectomized B6D2F1 hybrid mice along with the pathways to which they have been associated

Quantitative real-time PCR validated differences revealed in the bioinformatic analysis. Relative mRNA expression of APP and MAPT was greater in maters compared with non-maters, and SOD1, IMPA1, SCN1a, and PTEN was greater in the non-maters compared with maters (Table 3). Western blots of APP protein from POA and BNST tissues showed that normal APP was ∼40% higher in maters than non-maters (F (2,19) = 5.496, p < 0.05; Fig. 1). No differences in relative APP protein levels between sham castrated males and maters were noted. APP protein levels decline significantly after castration, but only in individuals that do not maintain their mating ability.

View this table:
  • View inline
  • View popup
Table 3.

mRNA levels as determined by quantitative RT-PCR for tissues from the mPOA and BNST of castrated non-maters and maters

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Representative Western blots from mPOA and BNST tissues are shown. Three individuals are depicted in each group; non-maters, maters and sham castrates (gonad-intact) male B6D2F1 mice. In the graph relative amounts of APP protein are adjusted for loading controls (β-actin). The non-maters have less APP protein than males in either other group, *p < 0.05.

Both before and after castration, males overexpressing APP displayed increased facilitation of MSB compared with controls. At almost every time point tested, a higher percentage of MSB was demonstrated by APP overexpressing mice than MSB observed in controls, and at several time points, statistical significance was reached (p < 0.05; Fig. 2 a–c). In addition, as revealed by the survival curves generated from the Mantel-Cox log-rank test, the survival curves for latencies to mount for APP transgenic mice were significantly different from than those of wild-type controls both before and after surgery, and the survival curve for ejaculation latencies were significantly different from controls before castration (p < 0.05; Fig. 2 d–i).

Figure 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2.

Sexual behavior in APP overexpressing mice and controls. a , Percentage of APP overexpressing mice and wild-type controls that displayed mounting both before and after castration. b , c , Intromissive behaviors ( b ) and percentage of males displaying an ejaculatory reflex ( c ). d–i , Kaplan-Meyer survivability plots showing the percentage of APP transgenic mice displaying mounts ( d , g ), intromissions ( e , h ), and ejaculations ( f , i ) both before castration ( d–f , respectively) and after castration ( g–i , respectively). *p < 0.05, significantly different from the other group.

Discussion

These data reveal a previously unknown functional relationship between individual differences in MSB and the normal APP gene and protein. Among the B6D2F1 hybrid mice, greater APP expression and protein in the mPOA and BNST is correlated with MSB lasting months after castration. Males with low APP expression and protein stopped displaying MSB a few weeks after castration. This observation is more than correlational; MSB in mice overexpressing the human APP gene was enhanced compared with control males. The APP gene is best known for mutations that are associated with neurodegenerative diseases such as Alzheimer's. Mutations of APP eventually result in impairment of synaptic plasticity and induce aberrant neuronal and axonal degeneration (for review, see Kim and Tsai, 2009). The normal APP gene is involved in cell survival and neuroprotection. It is likely that individual differences in cell survival and neuroprotection in critical populations of neurons of the mPOA and BNST are responsible for differences in male sexual behavior. Because the transgenic mice tested in our study overexpress APP ubiquitously, one must be cautious in attributing APP action to only the mPOA and BNST until we validate that the relative increased levels of APP is site specific.

Several transgenic mouse lines that overexpress human APP are available (Quon et al., 1991; Kammesheidt et al., 1992; Lamb et al., 1993; Mucke et al., 1994; Higgins et al., 1995; Andrä et al., 1996). In several of these lines, males tended to develop age-dependent cognitive decline (Van Dam et al., 2003), circadian activity disturbances (Vloeberghs et al., 2004), and increased aggression (Vloeberghs et al., 2006). Only one study investigated MSB in one of these transgenic lines (Vloeberghs et al., 2007), and this report is the first to examine MSB after castration in a transgenic mouse overexpressing human APP. In the one study that did investigate MSB in overexpressing APP mice, certain aspects of MSB, such as number of mounts, genital sniffing and licking, were not significantly different from wild-type controls; however, it is important to note that these mice, which exhibit a twofold overexpression of human APP, are a different transgenic line than the one we tested. The transgenic mouse line used in this study is known to overexpress human APP in brain at levels comparable to those noted in brains of castrated B6D2F1 hybrid males (Lamb et al., 1993). In addition, other aspects of MSB, such as frequencies of intromissions or ejaculations or latencies to mount, intromit or ejaculate were not reported (Vloeberghs et al., 2007).

Because APP affected MSB in gonad-intact mice, a relationship may exist between gonadal hormones, APP, and MSB. In vitro, estrogens increase secretion of soluble APPa (Xu et al., 1998) which regulates neuronal survival and neurite outgrowth. Perhaps estrogens reduce amyloid-β (Aβ) levels by promoting nonamyloidogenic processing and/or trafficking of APP (Greenfield et al., 2002). Most studies investigating the relationship between sex steroids and APP have focused on the abnormal accumulation of Aβ, a product of aberrant APP processing, which is believed to be the causative component of Alzheimer's disease pathogenesis. Anti-androgen treatments result in elevated plasma levels of Aβ, and a correlation is present between low T and elevated Aβ levels (for review, see Pike et al., 2009). Particularly during aging, as androgens decline, abnormal production of Aβ may occur as a result of dysfunctional APP gene. Other findings have indicated that androgen regulation of Aβ involves an androgen receptor-dependent mechanism requiring upregulation of the Aβ-catabolizing enzyme neprilysin (Yao et al., 2008). Because some of the B6D2F1 mice in the current study retain their ability to mate after castration and also have elevated APP, the degree to which this gene is regulated by steroid hormones is probably variable and may be thus related to observed variations in sexual behavior. Further tests are required to confirm the degree of neural protection and neural degeneration in the B6D2F1 mice.

One of the instructive aspects of our experiment is the use of several lines of genomic analyses to inform the selection of candidate gene pathways and genes. The bioinformatic analyses of gene expression arrays between castrated maters and non-maters yielded 532 genes that were differentially expressed, of which, 267 were downregulated and 265 were upregulated (supplemental Table S1, available at www.jneurosci.org as supplemental material). In conjunction with the data mined from the recombinant inbred lines of B6D2F1 mice, several other genes in addition to APP were found, and these were also associated with neurodegeneration and/or neuroprotection (Table 1). In this process, 532 candidates were reduced to six genes. While only one was directly tested here, the fact that expression of this gene was linked to the display of male sexual behavior is proof of principle and demonstrates that this is an instructive model for future gene expression studies.

It is highly likely that the other candidate genes discovered in this study, but not tested in transgenic mouse lines, regulate MSB. This is supported by our finding that the percentage of the castrated APP transgenic mice we tested was noticeably lower than previously reported in castrated B6D2F1 hybrid male mice 12 weeks after castration (Clemens et al., 1988; Park et al., 2009). Expression of phosphatase and tensin homolog (PTEN) was ∼40% lower in maters compared with non-maters. Inactivation of PTEN constitutively activates the PKB/AKT pathway which promotes cell survival. Although complete deletion of PTEN in mice results in embryonic lethality and heterozygous deletion causes increased cancer incidence (Stiles et al., 2004), region-specific deletion of PTEN has been performed. Mice with PTEN knock-out limited to mature neurons in the cerebral cortex and hippocampus (Kwon et al., 2006a) display abnormal dendritic and axonal growth and synapse number, abnormal social interactions and inappropriate responses to sensory stimuli (Kwon et al., 2006b). These conditional PTEN mutant mice do not demonstrate MSB, and fail to impregnate female mice (Kwon et al., 2006b). Whether a localized deletion of PTEN in the MPOA rather than the cerebral cortex and hippocampus would affect MSB has yet to be determined.

Expression of superoxide dismutase 1 (SOD1) was significantly downregulated ∼35% in maters compared with non-maters. SOD1 deficient mice have less astrogliosis and neurodegeneration (Beni et al., 2006). MAPT encodes the protein tau, which stabilizes microtubules to promote their assembly by binding to tubulin (Hirokawa, 1994). Defects in MAPT cause frontotemporal dementia due to atrophy with behavioral changes including deterioration of cognitive capacities and loss of memory (for review, see Rademakers et al., 2004). Currently we are assessing MSB in transgenic mice overexpressing tau and predict a behavioral phenotype similar to that reported for APP overexpressors.

Cell death and/or neuroprotection is occurring after castration in brain areas essential for male reproductive behaviors. Neuroprotection is more often studied in conjunction with cognitive rather than sexual behaviors. A link between APP, impaired cognition and increased sexual behavior is hinted at in the clinical literature, but has not been directly tested. Several clinical studies have reported inappropriate behavior and sexual disinhibition among cognitively impaired older men (Wallace and Safer, 2009) and there is a correlation between erectile dysfunction and Alzheimer's disease (Zeiss et al., 1990). Many men experience loss of libido and/or erectile function, in additional to cognitive decline during aging (Lunenfeld, 2006). In clinical populations of testicular and prostate cancer patients, treatments routinely require use of anti-androgen therapies and up to 85% of these men report decreased libido and sexual intimacy (Wilt et al., 2008). The present data suggest that a portion of this variability may be due to alterations in APP function; however, further studies are required to delineate the potential relationship between the inhibitory sexual effects of anti-androgen therapy for testicular and prostate cancer and decreased APP. We propose a model whereby APP gene regulation by androgens is reduced in certain individuals during normal aging. By virtue of a combination of other genetic, epigenetic and/or environmental factors, some males experience less of a decline in APP than others and it is these individuals that are most likely to retain their ability to display MSB. With increased longevity in normal and patient populations, new avenues for sex therapies that do not require steroid hormones are highly attractive for maintenance of normal sexual function.

Footnotes

  • This work was supported by National Institutes of Health Grants R01NS055218 (E.F.R.), K99HD056041 (J.H.P.), and a pilot grant from the Mellon Prostate Cancer Center at the University of Virginia (E.F.R.). We thank Salehin Rais, Alice Ding, and Aileen Wills for technical assistance.

  • Correspondence should be addressed to Dr. Jin Ho Park, Psychology Department, University of Massachusetts, Boston, 100 Morrissey Boulevard, Boston, MA 02125. JinHo.Park{at}umb.edu

References

  1. ↵
    1. Andrä K,
    2. Abramowski D,
    3. Duke M,
    4. Probst A,
    5. Wiederhold KH,
    6. Bürki K,
    7. Goedert M,
    8. Sommer B,
    9. Staufenbiel M
    (1996) Expression of APP in transgenic mice: a comparison of neuron-specific promoters. Neurobiol Aging 17:183–190.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Bagatell CJ,
    2. Heiman JR,
    3. Rivier JE,
    4. Bremner WJ
    (1994) Effects of endogenous testosterone and estradiol on sexual behavior in normal young men. J Clin Endocrinol Metab 78:711–716.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Beni SM,
    2. Tsenter J,
    3. Alexandrovich AG,
    4. Galron-Krool N,
    5. Barzilai A,
    6. Kohen R,
    7. Grigoriadis N,
    8. Simeonidou C,
    9. Shohami E
    (2006) CuZn-SOD deficiency, rather than overexpression, is associated with enhanced recovery and attenuated activation of NF-kappaB after brain trauma in mice. J Cereb Blood Flow Metab 26:478–490.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Benjamini Y,
    2. Hochberg Y
    (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 57:289–300.
    OpenUrl
  5. ↵
    1. Benjamini Y,
    2. Yekutieli D
    (2001) The control of false discovery rate in multiple testing under dependency. Ann Stat 29:1165–1188.
    OpenUrlCrossRef
  6. ↵
    1. Bolstad BM,
    2. Irizarry RA,
    3. Astrand M,
    4. Speed TP
    (2003) A comparison of normalization methods for high density oligonucleotide array data based on bias and variance. Bioinformatics 19:185–193.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Bronson FH
    (1989) Mammalian reproductive biology (University of Chicago, Chicago).
  8. ↵
    1. Clemens LG,
    2. Wee BE,
    3. Weaver DR,
    4. Roy EJ,
    5. Goldman BD,
    6. Rakerd B
    (1988) Retention of masculine sexual behavior following castration in male B6D2F1 mice. Physiol Behav 42:69–76.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Coquelin A
    (1991) Persistent sexual behavior in castrated, recombinant inbred mice. Biol Reprod 45:680–684.
    OpenUrlAbstract
  10. ↵
    1. Franklin KBJ,
    2. Paxinos G
    (1997) The mouse brain in stereotaxic coordinates (Academic, New York).
  11. ↵
    1. Gentleman R,
    2. Carey V,
    3. Dudoit S,
    4. Irizarry R,
    5. Huber W
    , eds(2005) Bioinformatics and computational biology solutions using R and bioconductor (Springer, New York).
  12. ↵
    1. Greenfield JP,
    2. Leung LW,
    3. Cai D,
    4. Kaasik K,
    5. Gross RS,
    6. Rodriguez-Boulan E,
    7. Greengard P,
    8. Xu H
    (2002) Estrogen lowers Alzheimer beta-amyloid generation by stimulating trans-Golgi network vesicle biogenesis. J Biol Chem 277:12128–12136.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Higgins LS,
    2. Rodems JM,
    3. Catalano R,
    4. Quon D,
    5. Cordell B
    (1995) Early Alzheimer disease-like histopathology increases in frequency with age in mice transgenic for beta-APP751. Proc Natl Acad Sci U S A 92:4402–4406.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Hirokawa N
    (1994) Microtubule organization and dynamics dependent on microtubule-associated proteins. Curr Opin Cell Biol 6:74–81.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Kammesheidt A,
    2. Boyce FM,
    3. Spanoyannis AF,
    4. Cummings BJ,
    5. Ortegón M,
    6. Cotman C,
    7. Vaught JL,
    8. Neve RL
    (1992) Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain. Proc Natl Acad Sci U S A 89:10857–10861.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Khatri P,
    2. Drăghici S
    (2005) Ontological analysis of gene expression data: current tools, limitations, and open problems. Bioinformatics 21:3587–3595.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Kim D,
    2. Tsai LH
    (2009) Bridging physiology and pathology in AD. Cell 137:997–1000.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Kwon CH,
    2. Zhou J,
    3. Li Y,
    4. Kim KW,
    5. Hensley LL,
    6. Baker SJ,
    7. Parada LF
    (2006a) Neuron-specific enolase-cre mouse line with cre activity in specific neuronal populations. Genesis 44:130–135.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Kwon CH,
    2. Luikart BW,
    3. Powell CM,
    4. Zhou J,
    5. Matheny SA,
    6. Zhang W,
    7. Li Y,
    8. Baker SJ,
    9. Parada LF
    (2006b) Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377–388.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Lamb BT,
    2. Sisodia SS,
    3. Lawler AM,
    4. Slunt HH,
    5. Kitt CA,
    6. Kearns WG,
    7. Pearson PL,
    8. Price DL,
    9. Gearhart JD
    (1993) Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected] Nat Genet 5:22–30.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Lunenfeld B
    (2006) Endocrinology of the aging male. Minerva Ginecol 58:153–170.
    OpenUrlPubMed
  22. ↵
    1. McGill TE,
    2. Manning A
    (1976) Genotype and retention of the ejaculatory reflex in castrated male mice. Anim Behav 24:507–518.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Micheal RP,
    2. Wilson M
    (1974) Effects of castration and hormone replacement in fully adult male rhesus monkeys (Macaca mulatta) Endocrinology 95:150–159.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Mucke L,
    2. Masliah E,
    3. Johnson WB,
    4. Ruppe MD,
    5. Alford M,
    6. Rockenstein EM,
    7. Forss-Petter S,
    8. Pietropaolo M,
    9. Mallory M,
    10. Abraham CR
    (1994) Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice. Brain Res 666:151–167.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Park JH,
    2. Bonthuis P,
    3. Ding A,
    4. Rais S,
    5. Rissman EF
    (2009) Androgen- and estrogen-independent regulation of copulatory behavior following castration in male B6D2F1 mice. Horm Behav 56:254–263.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Phoenix CH,
    2. Slob AK,
    3. Goy RW
    (1973) Effects of castration and replacement therapy on sexual behavior of adult male rhesuses. J Comp Physiol Psychol 84:472–481.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Pike CJ,
    2. Carroll JC,
    3. Rosario ER,
    4. Barron AM
    (2009) Protective actions of sex steroid hormones in Alzheimer's disease. Front Neuroendocrinol 30:239–258.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Quon D,
    2. Wang Y,
    3. Catalano R,
    4. Scardina JM,
    5. Murakami K,
    6. Cordell B
    (1991) Formation of beta-amyloid protein deposits in brains of transgenic mice. Nature 352:239–241.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Rademakers R,
    2. Cruts M,
    3. van Broeckhoven C
    (2004) The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24:277–295.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Selkoe DJ
    (1999) Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 399:A23–A31.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Sinchak K,
    2. Roselli CE,
    3. Clemens LG
    (1996) Levels of serum steroids, aromatase activity, and estrogen receptors in preoptic area, hypothalamus, and amygdala of B6D2F1 male house mice that differ in the display of copulatory behavior after castration. Behav Neurosci 110:593–602.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Sinha S,
    2. Lieberburg I
    (1999) Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci U S A 96:11049–11053.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Smyth GK
    (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:3.
    OpenUrl
  34. ↵
    1. Stiles B,
    2. Groszer M,
    3. Wang S,
    4. Jiao J,
    5. Wu H
    (2004) PTENless means more. Dev Biol 273:175–184.
    OpenUrlCrossRefPubMed
  35. ↵
    1. Van Dam D,
    2. D'Hooge R,
    3. Staufenbiel M,
    4. Van Ginneken C,
    5. Van Meir F,
    6. De Deyn PP
    (2003) Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci 17:388–396.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Vloeberghs E,
    2. Van Dam D,
    3. Engelborghs S,
    4. Nagels G,
    5. Staufenbiel M,
    6. De Deyn PP
    (2004) Altered circadian locomotor activity in APP23 mice: a model for BPSD disturbances. Eur J Neurosci 20:2757–2766.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Vloeberghs E,
    2. Van Dam D,
    3. Coen K,
    4. Staufenbiel M,
    5. De Deyn PP
    (2006) Aggressive male APP23 mice modeling behavioral alterations in dementia. Behav Neurosci 120:1380–1383.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Vloeberghs E,
    2. Van Dam D,
    3. Franck F,
    4. Staufenbiel M,
    5. De Deyn PP
    (2007) Mood and male sexual behaviour in the APP23 model of Alzheimer's disease. Behav Brain Res 180:146–151.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Wallace M,
    2. Safer M
    (2009) Hypersexuality among cognitively impaired older adults. Geriatr Nurs 30:230–237.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Wersinger SR,
    2. Sannen K,
    3. Villalba C,
    4. Lubahn DB,
    5. Rissman EF,
    6. De Vries GJ
    (1997) Masculine sexual behavior is disrupted in male and female mice lacking a functional estrogen receptor alpha gene. Horm Behav 32:176–183.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Wilt TJ,
    2. MacDonald R,
    3. Rutks I,
    4. Shamliyan TA,
    5. Taylor BC,
    6. Kane RL
    (2008) Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med 148:435–448.
    OpenUrlPubMed
  42. ↵
    1. Wu Z,
    2. Irizarry RA,
    3. Gentleman R,
    4. Martinez-Murillo F,
    5. Spencer F
    (2004) A model based background adjustment for oligonucleotide expression arrays. J Am Stat Assoc 99:909–917.
    OpenUrlCrossRef
  43. ↵
    1. Xu H,
    2. Gouras GK,
    3. Greenfield JP,
    4. Vincent B,
    5. Naslund J,
    6. Mazzarelli L,
    7. Fried G,
    8. Jovanovic JN,
    9. Seeger M,
    10. Relkin NR,
    11. Liao F,
    12. Checler F,
    13. Buxbaum JD,
    14. Chait BT,
    15. Thinakaran G,
    16. Sisodia SS,
    17. Wang R,
    18. Greengard P,
    19. Gandy S
    (1998) Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med 4:447–451.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Yao M,
    2. Nguyen TV,
    3. Rosario ER,
    4. Ramsden M,
    5. Pike CJ
    (2008) Androgens regulate neprilysin expression: role in reducing beta-amyloid levels. J Neurochem 105:2477–2488.
    OpenUrlCrossRef
  45. ↵
    1. Zeiss AM,
    2. Davies HD,
    3. Wood M,
    4. Tinklenberg JR
    (1990) The incidence and correlates of erectile problems in patients with Alzheimer's disease. Arch Sex Behav 19:325–331.
    OpenUrlCrossRefPubMed
Back to top

In this issue

The Journal of Neuroscience: 30 (30)
Journal of Neuroscience
Vol. 30, Issue 30
28 Jul 2010
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Amyloid β Precursor Protein Regulates Male Sexual Behavior
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
Amyloid β Precursor Protein Regulates Male Sexual Behavior
Jin Ho Park, Paul J. Bonthius, Houng-Wei Tsai, Stefan Bekiranov, Emilie F. Rissman
Journal of Neuroscience 28 July 2010, 30 (30) 9967-9972; DOI: 10.1523/JNEUROSCI.1988-10.2010

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
Amyloid β Precursor Protein Regulates Male Sexual Behavior
Jin Ho Park, Paul J. Bonthius, Houng-Wei Tsai, Stefan Bekiranov, Emilie F. Rissman
Journal of Neuroscience 28 July 2010, 30 (30) 9967-9972; DOI: 10.1523/JNEUROSCI.1988-10.2010
Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

Articles

  • Memory Retrieval Has a Dynamic Influence on the Maintenance Mechanisms That Are Sensitive to ζ-Inhibitory Peptide (ZIP)
  • Neurophysiological Evidence for a Cortical Contribution to the Wakefulness-Related Drive to Breathe Explaining Hypocapnia-Resistant Ventilation in Humans
  • Monomeric Alpha-Synuclein Exerts a Physiological Role on Brain ATP Synthase
Show more Articles

Behavioral/Systems/Cognitive

  • Influence of Reward on Corticospinal Excitability during Movement Preparation
  • Identification and Characterization of a Sleep-Active Cell Group in the Rostral Medullary Brainstem
  • Gravin Orchestrates Protein Kinase A and β2-Adrenergic Receptor Signaling Critical for Synaptic Plasticity and Memory
Show more Behavioral/Systems/Cognitive
  • Home
  • Alerts
  • Follow SFN on BlueSky
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Notice
  • Contact
  • Accessibility
(JNeurosci logo)
(SfN logo)

Copyright © 2025 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.