Effects of dihydrotestosterone on synaptic plasticity of the hippocampus in mild cognitive impairment male SAMP8 mice

Abstract

The current study focused on how dihydrotestosterone (DHT) regulates synaptic plasticity in the hippocampus of mild cognitive impairment male senescence-accelerated mouse prone 8 (SAMP8) mice. Five-month-old SAMP8 mice were divided into the control, castrated and castrated-DHT groups, in which the mice were castrated and treated with physiological doses of DHT for a period of 2 months. To determine the regulatory mechanisms of DHT in the cognitive capacity, the effects of DHT on the morphology of the synapse and the expression of synaptic marker proteins in the hippocampus were investigated using immunohistochemistry, qPCR and western blot analysis. The results showed that the expression of cAMP-response element binding protein (CREB), postsynaptic density protein 95 (PSD95), synaptophysin (SYN) and developmentally regulated brain protein (Drebrin) was reduced in the castrated group compared to the control group. However, DHT promoted the expression of CREB, PSD95, SYN and Drebrin in the hippocampus of the castrated-DHT group. Thus, androgen depletion impaired the synaptic plasticity in the hippocampus of SAMP8 and accelerated the development of Alzheimer's disease (AD)-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, DHT regulated synaptic plasticity in the hippocampus of mild cognitive impairment (MCI) SAMP8 mice and delayed the progression of disease to Alzheimer's dementia. In conclusion, androgen-based hormone therapy is a potentially useful strategy for preventing the progression of MCI in aging men. Androgens enhance synaptic markers (SYN, PSD95, and Drebrin), activate CREB, modulate the fundamental biology of synaptic structure, and lead to the structural changes of plasticity in the hippocampus, all of which result in improved cognitive function.

Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair

“…Treatment of gonadectomized rats with DHT or testosterone propionate but not with estradiol restored spine synapse density to similar levels of those found in intact males, suggesting a direct role of androgens through androgen receptors rather than indirectly via local estradiol biosynthesis in hippocampal synaptic plasticity (Leranth et al, 2003 ). Similar results were obtained in SAMP8 mice, an animal model of accelerated aging (Jia et al, 2016 ; Pan et al, 2016 ).…”

Synaptic Pruning in Alzheimer’s Disease: Role of the Complement System

“…The study authors conclude androgen-based hormone therapy is a potentially useful strategy for preventing the progression of MCI in aging men. Androgens enhance synaptic markers (SYN, PSD95, and Drebrin), activate CREB, modulate the fundamental biology of synaptic structure, and lead to the structural changes of plasticity in the hippocampus, all of which result in improved cognitive function [ 77 ].…”

Is testosterone perspective available for neurodegenerative diseases?

“…Testosterone is involved in the development of central nervous system and maintains the normal function during maturation [59]. The free form of testosterone can pass the bloodbrain barrier and stimulate the differentiation of neurons and neurite outgrowth increase [1].…”