Department of Neurosciences and the Medical University of South Carolina, Charleston, SC 29425, USA.
J Alzheimers Dis. 2011;23(3):471-89. doi: 10.3233/JAD-2010-101218.
Individuals with Down syndrome (DS) acquire Alzheimer's-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies.
唐氏综合征（DS）个体比年龄匹配的正常个体更早、更频繁地出现阿尔茨海默病（AD）样痴呆和相关神经病理学。然而，尚未发现生物学机制，目前针对 DS 或 AD 相关痴呆症的治疗方法有限。片段性三体 16（Ts65Dn）小鼠为许多与 DS 相关的退行性变化提供了有用的模型，包括认知缺陷、神经炎症和基底前脑胆碱能神经元变性。去甲肾上腺素能蓝斑核（LC）神经元的丧失是 AD 和 DS 中的早期事件，可能导致神经病理学变化。我们报告 Ts65Dn 小鼠 LC 神经元中的去甲肾上腺素（NE）表型逐渐丧失。为了确定 LC 退化是否导致 Ts65Dn 小鼠的记忆丧失和神经退行性变，我们在四个月大时用去甲肾上腺素能神经毒素 N-（2-氯乙基）-N-乙基-2-溴苄基胺（DSP-4；2 次剂量为 50mg/kg，ip）处理 Ts65Dn 小鼠，在工作记忆丧失之前。在八个月大时，用 DSP-4 处理的 Ts65Dn 小鼠的海马 NE 减少了 80%，同时海马神经炎症显著增加。去甲肾上腺素能耗竭还导致 Ts65Dn 小鼠的胆碱能神经元退化加速和记忆功能进一步受损。相比之下，DSP-4 对正常同窝小鼠的影响最小，这表明在 DS 小鼠模型中，NE 丧失对疾病有调节易感性。这些数据表明，去甲肾上腺素能退化可能在 DS 个体中发生的进行性记忆丧失、神经炎症和胆碱能丧失中起作用，为未来的临床研究提供了一种可能的治疗途径。
