Yan et al., Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer’s disease (2019)

https://www.ncbi.nlm.nih.gov/pubmed/30632505

An interesting study that illustrates the importance of the AR to hippocampal CA1 function through evidence in an Alzheimer’s disease rat model.

Abstract

Cognitive dysfunction in Alzheimer’s disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1-42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer’s disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer’s disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer’s disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.

As a bit of background, in humans, hippocampal CA1 neurons are crucial to autonoetic consciousness (internal perception of time and placing yourself in the future/past) continuity of self, the formation and retrieval of memories (Bartsch et al., 2011), emotional colouring (Tulving E, 1985) and a lot more including visual processing, anhedonia. Remarkably, in humans of both sexes, hippocampal AR is expressed of a similar magnitude to that of the prostate of BPH patients (Beyenburg et al., 2000), which of course finasteride is given to shrink by halting the formation of the metabolite 5alpha-DHT.

Posting with relevance to a study recently posted noting the impairment of 3xtg mice when treated with Finasteride.

This is coherent with previous evidence in mice that finasteride significantly reduced DHT in the hippocampus and reduced neurogenesis, influencing neuronal plasticity on a structural level with potential relevance to lasting depressive symptoms (Römer et al., 2010), although ordinarily this is reversed after cessation.

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Seems like the trifecta are all hitting memory.