Testosterone deficiency worsens mitochondrial dysfunction in APP/PS1 mice.

Area of Science:

• Neuroscience
• Endocrinology
• Mitochondrial Biology

Background:

• Testosterone (T) deficiency is linked to worsened cognitive impairment in Alzheimer's disease (AD) patients.
• Mitochondrial dysfunction is a critical hallmark and early event in AD pathogenesis.
• The impact of T deficiency on mitochondrial dysfunction in male AD patients remains unclear.

Purpose of the Study:

• To investigate the effects of T deficiency on mitochondrial dysfunction in male AD mouse models.
• To explore the underlying mechanisms of T's influence on mitochondrial health in AD.

Main Methods:

• Male APP/PS1 mice (AD model) underwent castration to induce T deficiency.
• Hippocampal mitochondrial function was assessed using spectrophotometry and flow cytometry.
• Gene and protein expression related to mitochondrial biogenesis and dynamics were analyzed via qPCR and Western blot.
• SH-SY5Y cells were used for in vitro mechanistic studies involving T, flutamide, and H2O2.

Main Results:

• T deficiency exacerbated cognitive deficits and hippocampal damage in male AD mice, correlating with increased oxidative stress and reduced mitochondrial function (membrane potential, Complex IV activity, ATP levels).
• T deficiency impaired mitochondrial biogenesis and dynamics at both mRNA and protein levels, leading to accumulation of defective mitochondria.
• In vitro studies confirmed T's protective effects against H2O2-induced mitochondrial dysfunction, with the androgen receptor (AR) pathway playing a crucial role.

Conclusions:

• Testosterone deficiency exacerbates hippocampal mitochondrial dysfunction in male AD mice by increasing defective mitochondria accumulation.
• Maintaining appropriate testosterone levels in early-stage AD may offer therapeutic benefits by enhancing mitochondrial biogenesis and dynamics, potentially delaying disease progression.