The early transition to Alzheimer’s disease is characterized by a period of accelerated brain atrophy that exceeds normal ageing. Identifying the molecular basis of this atrophy could facilitate the discovery of novel drug targets. The precursor of brain-derived neurotrophic factor, a well characterized neurotrophin, is increased in the hippocampus of aged rodents, while its mature isoform is relatively stable. This imbalance could increase the risk of Alzheimer’s disease by precipitating its pathological hallmarks. However, less is known about how relative levels of these isoforms change in middle-aged mice. In addition, the underlying mechanisms that might cause an imbalance are unknown. The main aim of this study was to determine how precursor brain-derived neurotrophic factor changes relative to its mature isoform with normal brain ageing in wild type mice. A secondary aim was to determine if signaling through the neurotrophin receptor, p75 influences this ratio. An increasing ratio was identified in several brain regions, except the hippocampus, suggesting a neurotrophic imbalance occurs as early as middle age. Some changes in receptors that mediate the isoforms effects were also identified, but these did not correspond with trends in the isoforms. Relative amounts of precursor brain-derived neurotrophic factor were mostly unchanged in mutant p75 mice. The lack of changes suggested that signaling through the receptor had no influence on the ratio.

早期转变为阿尔茨海默病的特点是脑萎缩加速，超过正常衰老速度。确定这种萎缩的分子基础可以促进新药物靶点的发现。脑源性神经营养因子的前体是一种特征明确的神经营养蛋白，在老年啮齿类动物的海马中含量增加，而其成熟亚型相对稳定。这种不平衡可能会加剧阿尔茨海默病的病理特征，从而增加患阿尔茨海默病的风险。然而，人们对中年小鼠中这些亚型的相对水平如何变化知之甚少。此外，可能导致不平衡的潜在机制尚不清楚。本研究的主要目的是确定在野生型小鼠的正常脑老化过程中，前体脑源性神经营养因子相对于其成熟异构体如何变化。第二个目的是确定通过神经营养蛋白受体 p75 发出的信号是否影响该比率。在除海马体之外的几个大脑区域中发现了一个不断增加的比例，这表明神经营养失衡早在中年就发生了。还发现了介导亚型效应的受体的一些变化，但这些变化与亚型的趋势并不相符。在突变 p75 小鼠中，前体脑源性神经营养因子的相对量基本没有变化。没有变化表明通过受体的信号传导对该比率没有影响。