Peng Shiyong, Garzon Diego J, Marchese Monica, Klein William, Ginsberg Stephen D, Francis Beverly M, Mount Howard T J, Mufson Elliott J, Salehi Ahmad, Fahnestock Margaret
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
J Neurosci. 2009 Jul 22;29(29):9321-9. doi: 10.1523/JNEUROSCI.4736-08.2009.
Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of AD. In vitro evidence suggests that amyloid-beta (A beta) contributes to BDNF downregulation in AD, but the specific A beta aggregation state responsible for this downregulation in vivo is unknown. In the present study, we examined cortical levels of BDNF mRNA in three different transgenic AD mouse models harboring mutations in APP resulting in A beta overproduction, and in a genetic mouse model of Down syndrome. Two of the three A beta transgenic strains (APP(NLh) and TgCRND8) exhibited significantly decreased cortical BDNF mRNA levels compared with wild-type mice, whereas neither the other strain (APP(swe)/PS-1) nor the Down syndrome mouse model (Ts65Dn) was affected. Only APP(NLh) and TgCRND8 mice expressed high A beta(42)/A beta(40) ratios and larger SDS-stable A beta oligomers (approximately 115 kDa). TgCRND8 mice exhibited downregulation of BDNF transcripts III and IV; transcript IV is also downregulated in AD. Furthermore, in all transgenic mouse strains, there was a correlation between levels of large oligomers, A beta(42)/A beta(40), and severity of BDNF decrease. These data show that the amount and species of A beta vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of A beta on decreased BDNF expression is specific to the aggregation state of A beta and is dependent on large oligomers.
在阿尔茨海默病（AD）进展的早期，大脑皮质中脑源性神经营养因子（BDNF）的表达下调。由于BDNF在神经元存活、突触可塑性和记忆中起关键作用，BDNF减少可能导致AD特有的突触和细胞丢失以及记忆缺陷。体外证据表明，淀粉样β蛋白（Aβ）在AD中导致BDNF下调，但体内导致这种下调的特定Aβ聚集状态尚不清楚。在本研究中，我们检测了三种不同的转基因AD小鼠模型（携带APP突变导致Aβ过量产生）以及唐氏综合征基因小鼠模型的皮质BDNF mRNA水平。与野生型小鼠相比，三种Aβ转基因品系中的两种（APP（NLh）和TgCRND8）皮质BDNF mRNA水平显著降低，而另一种品系（APP（swe）/PS-1）和唐氏综合征小鼠模型（Ts65Dn）均未受影响。只有APP（NLh）和TgCRND8小鼠表达高Aβ（42）/Aβ（40）比率和更大的SDS稳定Aβ寡聚体（约115 kDa）。TgCRND8小鼠表现出BDNF转录本III和IV的下调；转录本IV在AD中也下调。此外，在所有转基因小鼠品系中，大寡聚体水平、Aβ（42）/Aβ（40）与BDNF降低的严重程度之间存在相关性。这些数据表明，Aβ的量和种类在AD转基因小鼠模型中各不相同，且与BDNF水平呈负相关。这些发现还表明，Aβ对BDNF表达降低的影响特定于Aβ的聚集状态，且依赖于大寡聚体。
