Effects of testosterone on synaptic plasticity mediated by androgen receptors in male SAMP8 mice

Abstract

Synaptic changes are closely associated with cognitive deficits. In addition, testosterone (T) is known to exert regulative effects on synaptic plasticity. T may improve cognitive deficits in Alzheimer's disease (AD) patients, but the underlying mechanisms of androgenic action on cognitive performance remain unclear. The aim of this study was thus to examine the protective mechanism attributed to T on cognitive performance in an AD senescence, accelerated mouse prone 8 (SAMP8) animal model. Using Golgi staining to quantify the dendritic spine density in hippocampal CA1 region, molecular biomarkers of synapse function were analyzed using immunohistochemistry and western blot. T significantly increased the dendritic spine density in hippocampal CA1 region, while flutamide (F) inhibited these T-mediated effects. Immunohistochemistry and western blot analysis showed that the expression levels of brain derived neurotrophic factor (BDNF), postsynaptic density 95 (PSD-95), and p-cyclic-AMP response element binding protein (CREB)/CREB levels were significantly elevated in the T group, but F reduced the T-induced effects in these biomarkers to control levels. There were no significant differences in the expression levels of PSD-95, BDNF, and p-CREB/CREB between C and F. These findings indicate that the effects of T on improvement in synaptic plasticity were mediated via androgen receptor (AR). It is conceivable that new treatments targeted toward preventing synaptic pathology in AD may involve the use of androgen-acting drugs.

Genetics of Aggression in Alzheimer’s Disease (AD)

“…While the AR is abundantly expressed in both sexes, in AD expression of the AR has been found to be generally down-regulated, especially in aging males (Butchart et al, 2013; Dart et al, 2013; Fedotova et al, 2016; Jia et al, 2016). Interestingly the steroid-hormone testosterone-activated transcription factor-signaling AR (ANDR) is known to exert regulatory effects on synaptic plasticity and improve cognitive deficits in AD patients and transgenic rodent models for AD (TgAD) but the underlying mechanisms of androgenic action on cognitive performance remain unclear.…”

“…Interestingly the steroid-hormone testosterone-activated transcription factor-signaling AR (ANDR) is known to exert regulatory effects on synaptic plasticity and improve cognitive deficits in AD patients and transgenic rodent models for AD (TgAD) but the underlying mechanisms of androgenic action on cognitive performance remain unclear. Testosterone, via the AR, increases synaptophysin expression and improves synaptic plasticity and cognitive metrics in both Aβ42 peptide-hippocampal injected male rats and in the senescence-accelerated mouse prone 8 (SAMP8) TgAD murine model (Huo et al, 2016; Jia et al, 2016). In a recent double-blind, placebo-controlled, between-subject designed study, exogenous administration of testosterone to healthy adult men potentiated the AR-enriched hippocampus, amygdala and hypothalamus—anatomical regions known to be involved in the stimulation of aggressive behavior (Carré et al, 2016).…”

“…In a recent double-blind, placebo-controlled, between-subject designed study, exogenous administration of testosterone to healthy adult men potentiated the AR-enriched hippocampus, amygdala and hypothalamus—anatomical regions known to be involved in the stimulation of aggressive behavior (Carré et al, 2016). Several studies have further suggested that new treatments targeted toward preventing synaptic pathology in AD or in TgAD models may involve the use of androgen agonists and/or AR-acting drugs (Jia et al, 2016; Pan et al, 2016). Interestingly, polyprenol bioregulators such as Ropren (already used in AD treatment in Russia and Australia) and polyprenol 2,3-dihydro derivatives known as “ dolichols ” in gonadectomized rodents exhibit decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratios in the hippocampus compared with DA and serotonin (5-HT) levels, and are associated with increased anxiolytic (antianxiety) behaviors in treated animals (Sugden et al, 2009; Fedotova et al, 2016).…”

The Novel Implication of Androgen in Diabetes-induced Alzheimer's Disease

“…84 It has been reported that androgen receptors are involved in memory and learning by involving synapse function. 85,86 DHT could reduce the binding of N-methyl-D-aspartate (NMDA) receptor antagonist in hippocampus CA1 region, 87 and control NMDA mediated depolarization in pyramidal neurons. 88 Recent study reported that androgen inhibits reduction of hippocampal dendritic spine density in rats.…”

“…90 Also, testosterone could enhance the expression of brain derived neurotrophic factor, leading to improvement in hippocampal dendritic spine density, and the phosphorylation of CREB to enhance synaptic plasticity. 86 Androgens improve spine-synapse density in the CA1 of rodents. 91 Taken together, androgen could improve insulin resistance by binding androgen receptor in brain, enhance synaptic failure, and promote synaptogenesis in the AD brain.…”