Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Nat Neurosci. 2011 Jun;14(6):750-6. doi: 10.1038/nn.2801. Epub 2011 May 1.
Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.
淀粉样蛋白-β（Aβ）在特定脑区的沉积是阿尔茨海默病的病理学标志。然而，阿尔茨海默病中 Aβ沉积的区域易感性的机制尚不清楚。在此，我们提供的证据表明内源性神经元活动调节细胞外间隙（ISF）Aβ的区域浓度，从而驱动局部 Aβ聚集。通过体内微透析，我们发现 APP 转基因小鼠在斑块沉积前的几个脑区的 ISF Aβ浓度与随后的斑块沉积程度以及神经元活动的标志物乳酸盐浓度一致。此外，单侧触须刺激增加了 ISF Aβ，而单侧触须剥夺则减少了 ISF Aβ和乳酸盐浓度。长期单侧触须剥夺减少了淀粉样斑块的形成和生长。我们的结果提出了一个机制，可以解释阿尔茨海默病中特定脑区对 Aβ沉积的易感性。
