Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California, United States of America.
PLoS One. 2012;7(8):e39566. doi: 10.1371/journal.pone.0039566. Epub 2012 Aug 3.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin critically involved in cell survival, synaptic plasticity, and memory. BDNF has recently garnered significant attention as a potential therapeutic target for neurodegenerative diseases such as Alzheimer disease (AD), but emerging evidence suggests that BDNF may also be mechanistically involved in the pathogenesis of AD. AD patients have substantially reduced BDNF levels, which may be a result of Aβ and tau pathology. Recent evidence, however, indicates reduced BDNF levels may also serve to drive pathology in neuronal cultures, although this has not yet been established in vivo. To further investigate the mechanistic role of BDNF in AD, we generated 3xTg-AD mice with a heterozygous BDNF knockout (BDNF(+/-)) and analyzed Aβ and tau pathology. Aged 3xTg-AD/BDNF(+/-) mice have significantly reduced levels of brain BDNF, but have comparable levels of Aβ and tau pathology to 3xTg-AD/BDNF(+/+) mice. These findings indicate that chronic reduction of BDNF does not exacerbate the development of Aβ and tau pathology, and instead suggests the reduced BDNF levels found in AD patients are a consequence of these pathologies.
脑源性神经营养因子（BDNF）是一种对细胞存活、突触可塑性和记忆至关重要的神经营养因子。BDNF 最近作为阿尔茨海默病（AD）等神经退行性疾病的潜在治疗靶点引起了广泛关注，但新出现的证据表明，BDNF 也可能在 AD 的发病机制中发挥作用。AD 患者的 BDNF 水平显著降低，这可能是由于 Aβ 和 tau 病理学的结果。然而，最近的证据表明，BDNF 水平降低也可能在神经元培养物中驱动病理学，尽管这尚未在体内得到证实。为了进一步研究 BDNF 在 AD 中的作用机制，我们生成了携带杂合 BDNF 敲除（BDNF(+/-)）的 3xTg-AD 小鼠，并分析了 Aβ 和 tau 病理学。老年 3xTg-AD/BDNF(+/-) 小鼠的大脑 BDNF 水平显著降低，但与 3xTg-AD/BDNF(+/+) 小鼠相比，其 Aβ 和 tau 病理学水平相当。这些发现表明，BDNF 的慢性减少不会加剧 Aβ 和 tau 病理学的发展，而是表明 AD 患者中发现的 BDNF 水平降低是这些病理学的结果。
