Schultz Nina, Byman Elin, Fex Malin, Wennström Malin
1 Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
2 Unit for Molecular Metabolism, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.
J Cereb Blood Flow Metab. 2017 Apr;37(4):1470-1482. doi: 10.1177/0271678X16657093. Epub 2016 Jan 1.
Amylin, a pancreatic β-cell-derived peptide hormone, forms inclusions in brain microvessels of patients with dementia who have been diagnosed with type 2 diabetes and Alzheimer's disease. The cellular localization of these inclusions and the consequences thereof are not yet known. Using immunohistochemical staining of hippocampus and parahippocampal cortex from patients with Alzheimer's disease and non-demented controls, we show that amylin cell inclusions are found in pericytes. The number of amylin cell inclusions did not differ between patients with Alzheimer's disease and controls, but amylin-containing pericytes displayed nuclear changes associated with cell death and reduced expression of the pericyte marker neuron-glial antigen 2. The impact of amylin on pericyte viability was further demonstrated in in vitro studies, which showed that pericyte death increased in presence of fibril- and oligomer amylin. Furthermore, oligomer amylin increased caspase 3/7 activity, reduced lysate neuron-glial antigen 2 levels and impaired autophagy. Our findings contribute to increased understanding of how aggregated amylin affects brain vasculature and highlight amylin as a potential factor involved in microvascular pathology in dementia progression.
胰淀素是一种由胰腺β细胞产生的肽类激素，在已被诊断患有2型糖尿病和阿尔茨海默病的痴呆患者的脑微血管中形成包涵体。这些包涵体的细胞定位及其后果尚不清楚。通过对阿尔茨海默病患者和非痴呆对照者的海马体和海马旁回皮质进行免疫组织化学染色，我们发现胰淀素细胞包涵体存在于周细胞中。阿尔茨海默病患者和对照者之间的胰淀素细胞包涵体数量没有差异，但含有胰淀素的周细胞显示出与细胞死亡相关的核变化以及周细胞标志物神经胶质抗原2的表达降低。体外研究进一步证明了胰淀素对周细胞活力的影响，结果表明在存在纤维状和寡聚体胰淀素的情况下周细胞死亡增加。此外，寡聚体胰淀素增加了半胱天冬酶3/7的活性，降低了裂解物中神经胶质抗原2的水平并损害了自噬。我们的研究结果有助于加深对聚集的胰淀素如何影响脑血管系统的理解，并突出了胰淀素作为痴呆进展中微血管病理的一个潜在因素。
