Protective Effects of Testosterone on Presynaptic Terminals against Oligomericβ-Amyloid Peptide in Primary Culture of Hippocampal Neurons

Abstract

Increasing lines of evidence support that testosterone may have neuroprotective effects. While observational studies reported an association between higher bioavailable testosterone or brain testosterone levels and reduced risk of Alzheimer's disease (AD), there is limited understanding of the underlying neuroprotective mechanisms. Previous studies demonstrated that testosterone could alleviate neurotoxicity induced by β-amyloid (Aβ), but these findings mainly focused on neuronal apoptosis. Since synaptic dysfunction and degeneration are early events during the pathogenesis of AD, we aim to investigate the effects of testosterone on oligomeric Aβ-induced synaptic changes. Our data suggested that exposure of primary cultured hippocampal neurons to oligomeric Aβ could reduce the length of neurites and decrease the expression of presynaptic proteins including synaptophysin, synaptotagmin, and synapsin-1. Aβ also disrupted synaptic vesicle recycling and protein folding machinery. Testosterone preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated Aβ-induced impairment of synaptic exocytosis. By using letrozole as an aromatase antagonist, we further demonstrated that the effects of testosterone on exocytosis were unlikely to be mediated through the estrogen receptor pathway. Furthermore, we showed that testosterone could attenuate Aβ-induced reduction of HSP70, which suggests a novel mechanism that links testosterone and its protective function on Aβ-induced synaptic damage. Taken together, our data provide further evidence on the beneficial effects of testosterone, which may be useful for future drug development for AD.

Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

“…Some examples are presynaptic proteins synaptophysin (SYP), synaptopbrevin, SNAP‐25, rab 3A, and postsynaptic proteins such as syntaxin, drebrin, and PSD‐95 . This observation was reproduced in AD animal models and in vitro models . In early stages, again coincident with mild cognitive symptoms, many of these were found to be transiently increased .…”

“…[25][26][27][28][29] This observation was reproduced in AD animal models [30][31][32] and in vitro models. [33][34][35] In early stages, again coincident with mild cognitive symptoms, many of these were found to be transiently increased. 26,29,36 Among others, synaptic vesicle component SYP has been a distinctive marker for evaluating synaptic conditions.…”

Is testosterone perspective available for neurodegenerative diseases?

“…Age-related loss of sex steroid hormones (estrogen and testosterone) has been correlated with the enhanced risk for AD in both females and males [35]. The decrease of testosterone levels is correlated with enhanced levels of Aβ peptides, neuronal cell death, and hyperphosphorylation of tau proteins [36]. For these reasons, the loss of testosterone and the metabolites, DHT and estradiol might be risk factors for the pathogenesis of AD and dementia.…”

“…Synaptic vesicle proteins are very important for dopamine neurotransmission and synaptic vesicle proteins recirculation is reduced by Aβ oligomers. It has been demonstrated that exogenous testosterone turns loss of synaptic vesicle proteins, Aβ-stimulated neurite damage, and exocytosis dysfunction [36]. Moreover, it has been shown that testosterone can enhance p75-nerve growth factor receptor and NGF and reduce the concentrations of beta-amyloid peptides in rat neurons [26].…”

Sexual dimorphism of frailty and cognitive impairment: Potential underlying mechanisms

“…An optimal level of testosterone exhibits neuroprotective effects by a high density of androgen receptors in the hippocampus and its associated cortical areas (105,106). Testosterone may promote synaptic plasticity (107,108), protect against apoptosis in hippocampal neurons (109) and attenuate Ab toxicity (110). The age-associated decline in androgen levels appears earlier compared with the neuropathological diagnosis of AD and the decline in androgen levels may be a cause of AD.…”