Testosterone reduces hippocampal synaptic damage in an androgen receptor-independent manner.

Aging-related reduction in androgen levels may be a possible risk factor for neurodegenerative diseases and contribute to cognitive impairment. Androgens may affect synaptic function and cognition in an androgen receptor (AR)-independent manner; however, the mechanisms connecting theses effects are unknown. Therefore, we used testicular feminization mutation (Tfm) male mice, a model with AR mutation, to test the effects of testosterone on synaptic function and cognition. Our results showed that testosterone ameliorated spatial memory deficit and neuronal damage, and increased dendritic spines density and postsynaptic density protein 95 (PSD95) and glutamate receptor 1 (GluA1) expression in the hippocampus of Tfm male mice. And these effects of testosterone were not inhibited by anastrozole, which suppressed conversion of testosterone to estradiol. Mechanistically, testosterone activated the extracellular signal-related kinase 1/2 (Erk1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) in the hippocampus of Tfm male mice. Meanwhile, Erk1/2 inhibitor SCH772984 blocked the upregulation of phospho-CREB, PSD95, and GluA1 induced by testosterone in HT22 cells pretreated with flutamide, an androgen antagonist. Collectively, our data indicate that testosterone may ameliorate hippocampal synaptic damage and spatial memory deficit by activating the Erk1/2-CREB signaling pathway in an AR-independent manner.

CaMKII is a modulator in neurodegenerative diseases and mediates the effect of androgen on synaptic protein PSD95.

Androgens rapidly regulate synaptic plasticity in hippocampal neurones, but the underlying mechanisms remain unclear. In this study, we carried out a comprehensive bioinformatics analysis of functional similarities between androgen receptor (AR) and the synaptic protein postsynaptic density 95 (PSD95) to evaluate the effect. Using different measurements and thresholds, we obtained consistent results illustrating that the two proteins were significantly involved in similar pathways. We further identified CaMKII plays a critical role in mediating the rapid effect of androgen and promoting the expression of PSD95. We used mouse hippocampal neurone HT22 cells as a cell model to investigate the effect of testosterone (T) on intracellular Ca2+ levels and the mechanism. Calcium imaging experiments showed that intracellular Ca2+ increased to a peak due to calcium influx in the extracellular fluid through L-type and N-type voltage-gated calcium channels when HT22 cells were treated with 100 nM T for 20 min. Subsequently, we investigated whether the Ca2+/CaMKII signaling pathway mediates the rapid effect of T, promoting the expression of the synaptic protein PSD95. Immunofluorescence cytochemical staining and western blotting results showed that T promoted CaMKII phosphorylation by rapidly increasing extracellular Ca2+ influx, thus increasing PSD95 expression. This study demonstrated that CaMKII acts as a mediator assisting androgen which regulates the synaptic protein PSD95Also, it provides evidence for the neuroprotective mechanisms of androgens in synaptic plasticity and reveals the gated and pharmacological mechanisms of the voltage-gated Ca2+ channel family for androgen replacement therapy.

Association of Androgens and Gonadotropins with Amnestic Mild Cognitive Impairment and Probable Alzheimer's Disease in Chinese Elderly Men.

BACKGROUND: Age-related hormone changes play important roles in cognitive decline in older men, and apolipoprotein E ɛ4 (APOEɛ4) is a risk factor for Alzheimer's disease (AD). OBJECTIVE: This study aimed to investigate the interactive role of androgen decline and APOEɛ4 genotype in the pathogenesis of amnestic mild cognitive impairment (aMCI) and AD. METHODS: In total, 576 elderly men over 65 years old from communities in Shijiazhuang were enrolled in this study, including 243 with normal cognition (NC), 271 with aMCI, and 62 with probable AD. Cognitive function was evaluated with a battery of neuropsychological tests. The serum levels of androgen and gonadotropin were detected by ELISA and chemiluminescence immunoassay. RESULTS: The levels of free testosterone (FT) and dihydrotestosterone (DHT) were lower in the aMCI group (p < 0.05), and even lower in the AD group (p < 0.001), but the levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH)were higher in AD group (p < 0.01), comparing with that in NC or aMCI group. The interaction of lower FT or DHT levels with APOEɛ4 had a risk role in global cognitive impairment (p < 0.05). The area under the curve (AUC) of the ROC curve for predicting aMCI by serum FT levels was 0.745. CONCLUSION: These results indicated that the interaction of androgen decline and APOEɛ4 genotype play a role in aMCI and AD. Serum FT levels have a predictive value for aMCI and might be a potential biomarker for prodromal AD.

Non-genomic mechanisms mediate androgen-induced PSD95 expression.

The non-genomic actions of androgen-induced synaptic plasticity have been extensively studied. However, the underlying mechanisms remain controversial. We recently found that testosterone-fetal bovine serum albumin (T-BSA), a cell membrane-impermeable complex, led to a rapid increase in the postsynaptic density 95 (PSD95) protein level through a transcription-independent mechanism in mouse hippocampal HT22 cells. Using T-BSA conjugated FITC, we verified the presence of membrane androgen-binding sites. Here, we show that T-BSA-induced PSD95 expression is mediated by G-protein-coupled receptor (GPCR)-zinc transporter ZIP9 (SLC39A9), one of the androgen membrane binding sites, rather than the membrane-localized androgen receptor. Furthermore, we found that T-BSA induced an interaction between ZIP9 and Gnα11 that lead to the phosphorylation of Erk1/2 MAPK and eIF4E, which are critical in the mRNA translation process. The PSD95 and p-eIF4E expression decreased when knockdown of ZIP9 or Gnα11 expression or inhibition of Erk1/2 activation. Taken together, these findings suggest that ZIP9 mediates the non-genomic action of androgen on synaptic protein PSD95 synthesis through the Gnα11/Erk1/2/eIF4E pathway in HT22 cells. This novel mechanism provides a theoretical basis to understand the neuroprotective mechanism of androgen.