Blockade of caspase-1 increases neurogenesis in the aged hippocampus
Blockade of caspase-1 increases neurogenesis in the aged hippocampus
复制标题
DOI：
10.1111/j.1460-9568.2007.05875.x
复制
发表时间：
2007-11-01
影响因子：
3.4
通讯作者：
Bickford, Paula C.
中科院分区：
文献类型：
--
作者：
Gemma, Carmelina;Bachstetter, Adam D.;Bickford, Paula C.
成年海马神经发生随着年龄的增长而显著下降，并且已经提出这种下降有助于与年龄相关的记忆缺陷。中枢炎症对与衰老相关的神经发生的减少有重要作用。白细胞介素-1 β是一种促炎细胞因子，最初作为无活性前体合成，其被半胱天冬酶-1切割以产生生物活性成熟形式。IL-1 β是否影响老年海马体中的神经发生尚不清楚。在此，我们分析了在IL-1 β裂解被半胱天冬酶-1抑制剂Ac-YVAD-CMK（10 pmol）抑制的动物中5-溴-2-脱氧尿苷（BrdU; 50 mg/kg）阳性的细胞。老年（22个月）和年轻（4个月）大鼠接受Ac-YVAD-CMK 28天脑室内通过脑输液套管连接到渗透微型泵。从第14天开始，动物连续5天每天接受BrdU注射。最后一次注射BrdU后10天进行的无偏体视学分析显示，在5天内产生的新生细胞总数在年轻大鼠中高于老年大鼠。此外，与老年对照组相比，Ac-YVAD-CMK治疗的老年大鼠的BrdU标记细胞数量增加了53%。进行免疫荧光研究以鉴定BrdU标记的细胞的细胞表型。BrdU阳性细胞的增加不是由于颗粒下区表达神经元或神经胶质表型的细胞比例的变化。这些发现表明，侧脑室注射Ac-YVAD-CMK逆转了与衰老相关的海马神经发生的减少。
Adult hippocampal neurogenesis dramatically decreases with increasing age, and it has been proposed that this decline contributes to age-related memory deficits. Central inflammation contributes significantly to the decrease in neurogenesis associated with ageing. Interleukin-1 beta is a proinflammatory cytokine initially synthesized as an inactive precursor that is cleaved by caspase-1 to generate the biologically active mature form. Whether IL-1 beta affects neurogenesis in the aged hippocampus is unknown. Here we analysed cells positive for 5-bromo-2-deoxyuridine (BrdU; 50 mg/kg) in animals in which cleavage of IL-1 beta was inhibited by the caspase-1 inhibitor Ac-YVAD-CMK (10 pmol). Aged (22 months) and young (4 months) rats received Ac-YVAD-CMK for 28 days intracerebroventricularly through a brain infusion cannula connected to an osmotic minipump. Starting on day 14, animals received a daily injection of BrdU for five consecutive days. Unbiased stereology analyses performed 10 days after the last injection of BrdU revealed that the total number of newborn cells generated over a 5-day period was higher in young rats than in aged rats. In addition, there was a 53% increase in the number of BrdU-labelled cells of the aged Ac-YVAD-CMK-treated rats compared to aged controls. Immunofluorescence studies were performed to identify the cellular phenotype of BrdU-labelled cells. The increase in BrdU-positive cells was not due to a change in the proportion of cells expressing neuronal or glial phenotypes in the subgranular zone. These findings demonstrate that the intracerebroventricular administration of Ac-YVAD-CMK reversed the decrease in hippocampal neurogenesis associated with ageing.