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Protective effects of testosterone on presynaptic terminals against oligomeric ?-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 ?-amyloid (A?), 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 A?-induced synaptic changes. Our data suggested that exposure of primary cultured hippocampal neurons to oligomeric A? could reduce the length of neurites and decrease the expression of presynaptic proteins including synaptophysin, synaptotagmin, and synapsin-1. A? also disrupted synaptic vesicle recycling and protein folding machinery. Testosterone preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated A?-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 A?-induced reduction of HSP70, which suggests a novel mechanism that links testosterone and its protective function on A?-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.

SUBMITTER: Lau CF

PROVIDER: S-EPMC4086619 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Protective effects of testosterone on presynaptic terminals against oligomeric β-amyloid peptide in primary culture of hippocampal neurons.

Lau Chi-Fai CF Ho Yuen-Shan YS Hung Clara Hiu-Ling CH Wuwongse Suthicha S Poon Chun-Hei CH Chiu Kin K Yang Xifei X Chu Leung-Wing LW Chang Raymond Chuen-Chung RC

BioMed research international 20140618

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. Sinc ...[more]

PMID: 25045655

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Project description:Elimination of the Kv1.3 voltage-dependent potassium channel gene produces striking changes in the function of the olfactory bulb, raising the possibility that this channel also influences other sensory systems. We have examined the cellular and subcellular localization of Kv1.3 in the medial nucleus of the trapezoid body (MNTB) in the auditory brainstem, a nucleus in which neurons fire at high rates with high temporal precision. A clear gradient of Kv1.3 immunostaining along the lateral to medial tonotopic axis of the MNTB was detected. Highest levels were found in the lateral region of the MNTB, which corresponds to neurons that respond selectively to low-frequency auditory stimuli. Previous studies have demonstrated that MNTB neurons and their afferent inputs from the cochlear nucleus express three other members of the Kv1 family, Kv1.1, Kv1.2, and Kv1.6. Nevertheless, confocal microscopy of MNTB sections coimmunostained for Kv1.3 with these subunits revealed that the distribution of Kv1.3 differed significantly from other Kv1 family subunits. In particular, no axonal staining of Kv1.3 was detected, and most prominent labeling was in structures surrounding the somata of the principal neurons, suggesting specific localization to the large calyx of Held presynaptic endings that envelop the principal cells. The presence of Kv1.3 in presynaptic terminals was confirmed by coimmunolocalization with the synaptic markers synaptophysin, syntaxin, and synaptotagmin and by immunogold electron microscopy. Kv1.3 immunogold particles in the terminals were arrayed along the plasma membrane and on internal vesicular structures. To confirm these patterns of staining, we carried out immunolabeling on sections from Kv1.3(-/-) mice. No immunoreactivity could be detected in Kv1.3(-/-) mice either at the light level or in immunogold experiments. The finding of a tonotopic gradient in presynaptic terminals suggests that Kv1.3 may regulate neurotransmitter release differentially in neurons that respond to different frequencies of sound.

Dataset Information

Protective effects of testosterone on presynaptic terminals against oligomeric ?-amyloid peptide in primary culture of hippocampal neurons.

Publications

Protective effects of testosterone on presynaptic terminals against oligomeric β-amyloid peptide in primary culture of hippocampal neurons.

Similar Datasets

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