Wyss-Coray T, Lin C, Yan F, Yu G Q, Rohde M, McConlogue L, Masliah E, Mucke L
Gladstone Institute of Neurological Disease, University of California, San Francisco, California, USA.
Nat Med. 2001 May;7(5):612-8. doi: 10.1038/87945.
Abnormal accumulation of the amyloid-beta peptide (Abeta) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor beta1 (TGF-beta1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Abeta deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-beta1 production in aged transgenic mice expressing the human beta-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Abeta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-beta1, Abeta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Abeta immunoreactivity associated with parenchymal plaques was inversely correlated with Abeta in blood vessels and cortical TGF-beta1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-beta1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-beta1 stimulated Abeta clearance in microglial cell cultures. These results demonstrate that TGF-beta1 is an important modifier of amyloid deposition in vivo and indicate that TGF-beta1 might promote microglial processes that inhibit the accumulation of Abeta in the brain parenchyma.
β-淀粉样肽（Aβ）在大脑中的异常蓄积似乎对所有形式的阿尔茨海默病（AD）的发病机制都至关重要，但散发性AD的潜在机制仍不清楚。转化生长因子β1（TGF-β1）是大脑对损伤和炎症反应的关键调节因子，已被证明与体内Aβ沉积有关。在此，我们证明，在表达人β-淀粉样前体蛋白（hAPP）的老年转基因小鼠中，星形胶质细胞TGF-β1生成量适度增加会导致实质淀粉样斑块数量减少三倍，海马体和新皮质中Aβ总负荷减少50%，以及营养不良性神经突数量减少。在表达hAPP和TGF-β1的小鼠中，Aβ大量积聚在脑血管中，但不在实质斑块中。在AD患者中，与实质斑块相关的Aβ免疫反应性与血管中的Aβ及皮质TGF-β1 mRNA水平呈负相关。hAPP/TGF-β1小鼠实质斑块的减少与小胶质细胞的强烈激活及炎症介质的增加有关。重组TGF-β1刺激小胶质细胞培养物中的Aβ清除。这些结果表明，TGF-β1是体内淀粉样沉积的重要调节因子，并表明TGF-β1可能促进抑制Aβ在脑实质中积聚的小胶质细胞过程。
