Rosario Emily R, Carroll Jenna C, Oddo Salvatore, LaFerla Frank M, Pike Christian J
Neuroscience Graduate Program, University of Southern California, Los Angeles, California 90089, USA.
J Neurosci. 2006 Dec 20;26(51):13384-9. doi: 10.1523/JNEUROSCI.2514-06.2006.
Normal age-related testosterone depletion in men is a recently identified risk factor for Alzheimer's disease (AD), but how androgen loss affects the development of AD is unclear. To investigate the relationship between androgen depletion and AD, we compared how androgen status affects the progression of neuropathology in the triple transgenic mouse model of AD (3xTg-AD). Adult male 3xTg-AD mice were sham gonadectomized (GDX) or GDX to deplete endogenous androgens and then exposed for 4 months to either the androgen dihydrotestosterone (DHT) or to placebo. In comparison to gonadally intact 3xTg-AD mice, GDX mice exhibited robust increases in the accumulation of beta-amyloid (Abeta), the protein implicated as the primary causal factor in AD pathogenesis, in both hippocampus and amygdala. In parallel to elevated levels of Abeta, GDX mice exhibited significantly impaired spontaneous alternation behavior, indicating deficits in hippocampal function. Importantly, DHT treatment of GDX 3xTg-AD mice attenuated both Abeta accumulation and behavioral deficits. These data demonstrate that androgen depletion accelerates the development of AD-like neuropathology, suggesting that a similar mechanism may underlie the increased risk for AD in men with low testosterone. In addition, our finding that DHT protects against acceleration of AD-like neuropathology predicts that androgen-based hormone therapy may be a useful strategy for the prevention and treatment of AD in aging men.
男性正常的与年龄相关的睾酮耗竭是最近确定的阿尔茨海默病（AD）的一个风险因素，但雄激素丧失如何影响AD的发展尚不清楚。为了研究雄激素耗竭与AD之间的关系，我们比较了雄激素状态如何影响AD三重转基因小鼠模型（3xTg-AD）中神经病理学的进展。成年雄性3xTg-AD小鼠进行假去势（GDX）或去势以耗尽内源性雄激素，然后将其暴露于雄激素双氢睾酮（DHT）或安慰剂中4个月。与性腺完整的3xTg-AD小鼠相比，去势小鼠在海马体和杏仁核中β-淀粉样蛋白（Aβ）的积累均显著增加，Aβ被认为是AD发病机制中的主要致病因素。与Aβ水平升高同时，去势小鼠表现出自发交替行为明显受损，表明海马功能存在缺陷。重要的是，对去势的3xTg-AD小鼠进行DHT治疗可减轻Aβ积累和行为缺陷。这些数据表明，雄激素耗竭会加速AD样神经病理学的发展，这表明低睾酮男性患AD风险增加可能存在类似机制。此外，我们发现DHT可防止AD样神经病理学加速发展，这预示着基于雄激素的激素疗法可能是预防和治疗老年男性AD的一种有用策略。
