Kolecki Radek, Lafauci Giuseppe, Rubenstein Richard, Mazur-Kolecka Bozena, Kaczmarski Wojciech, Frackowiak Janusz
Lehigh University, Bethlehem, PA, USA.
Acta Neuropathol. 2008 Oct;116(4):419-24. doi: 10.1007/s00401-008-0380-4. Epub 2008 May 16.
Stimulation of endogenous neurogenesis and transplantation of neuronal progenitors (NPs) are considered in therapy of neuronal loss associated with ageing and in neurodegenerative diseases with amyloidosis-beta, for example, Alzheimer's disease and Down syndrome. However, the influence of brain environment altered by ageing and deposits of amyloid-beta on proliferation of endogenous and transplanted NPs and their maturation into neurons is not understood. We studied the effect of ageing and development of amyloidosis-beta on proliferation of NPs (1) in the granular layer of dentate gyrus in the hippocampi of APP-transgenic mice (Tg9291) before and after development of amyloidosis-beta, that is, in mice aged 2-4 months and 9-12 months, respectively, and in age-matched controls; and (2) in culture of NPs isolated from brains of control and Tg9291 mice, aged 3 and 9 months. We found that the number of proliferating NPs was reduced in 9-12-months-old mice, in both control and Tg9291, as compared to 2-4-months-old mice. However, the 9-12-months-old Tg9291 mice with amyloid-beta deposits had significantly more proliferating NPs than the age-matched controls. NPs proliferation in culture did not depend on the age, presence of APP-transgene, and amyloidosis-beta in donors. The results indicate that the local brain environment influences proliferation of NPs, and development of amyloidosis-beta in the neurogenic regions attenuates the age-associated reduction of proliferation of NPs. Identification of the responsible mechanisms may be important for development of a successful therapy of neurodegeneration caused by amyloidosis-beta.
内源性神经发生的刺激和神经元祖细胞（NP）的移植被认为可用于治疗与衰老相关的神经元丢失以及患有β-淀粉样蛋白的神经退行性疾病，例如阿尔茨海默病和唐氏综合征。然而，衰老和β-淀粉样蛋白沉积所改变的脑环境对内源性和移植的NP增殖及其向神经元成熟的影响尚不清楚。我们研究了衰老和β-淀粉样蛋白形成对NP增殖的影响：（1）在APP转基因小鼠（Tg9291）海马齿状回颗粒层中，分别在β-淀粉样蛋白形成之前和之后，即2至4个月龄和9至12个月龄的小鼠以及年龄匹配的对照小鼠中；（2）在从3个月和9个月龄的对照和Tg9291小鼠大脑中分离出的NP培养物中。我们发现，与2至4个月龄的小鼠相比，9至12个月龄的对照和Tg9291小鼠中增殖的NP数量减少。然而，具有β-淀粉样蛋白沉积的9至12个月龄Tg9291小鼠的增殖NP明显多于年龄匹配的对照。培养物中NP的增殖不依赖于供体的年龄、APP转基因的存在和β-淀粉样蛋白的形成。结果表明，局部脑环境影响NP的增殖，神经源性区域中β-淀粉样蛋白的形成减弱了与年龄相关的NP增殖减少。确定相关机制可能对开发成功治疗由β-淀粉样蛋白引起的神经退行性变的疗法很重要。
