Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Advanced Imaging Core, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
Neurobiol Dis. 2022 Nov;174:105887. doi: 10.1016/j.nbd.2022.105887. Epub 2022 Oct 6.
We have previously reported that the single transmembrane protein Dipeptidyl Peptidase Like 6 (DPP6) impacts neuronal and synaptic development. DPP6-KO mice are impaired in hippocampal-dependent learning and memory and exhibit smaller brain size. Recently, we have described novel structures in hippocampal area CA1 in aging mice, apparently derived from degenerating presynaptic terminals, that are significantly more prevalent in DPP6-KO mice compared to WT mice of the same age and that these structures were observed earlier in development in DPP6-KO mice. These novel structures appear as clusters of large puncta that colocalize NeuN, synaptophysin, and chromogranin A, and also partially label for MAP2, amyloid β, APP, α-synuclein, and phosphorylated tau, with synapsin-1 and VGluT1 labeling on their periphery. In this current study, using immunofluorescence and electron microscopy, we confirm that both APP and amyloid β are prevalent in these structures; and we show with immunofluorescence the presence of similar structures in humans with Alzheimer's disease. Here we also found evidence that aging DPP6-KO mutants show additional changes related to Alzheimer's disease. We used in vivo MRI to show reduced size of the DPP6-KO brain and hippocampus. Aging DPP6-KO hippocampi contained fewer total neurons and greater neuron death and had diagnostic biomarkers of Alzheimer's disease present including accumulation of amyloid β and APP and increase in expression of hyper-phosphorylated tau. The amyloid β and phosphorylated tau pathologies were associated with neuroinflammation characterized by increases in microglia and astrocytes. And levels of proinflammatory or anti-inflammatory cytokines increased in aging DPP6-KO mice. We finally show that aging DPP6-KO mice display circadian dysfunction, a common symptom of Alzheimer's disease. Together these results indicate that aging DPP6-KO mice show symptoms of enhanced neurodegeneration reminiscent of dementia associated with a novel structure resulting from synapse loss and neuronal death. This study continues our laboratory's work in discerning the function of DPP6 and here provides compelling evidence of a direct role of DPP6 in Alzheimer's disease.
我们之前曾报道过，单跨膜蛋白二肽基肽酶 6（DPP6）会影响神经元和突触的发育。DPP6 敲除小鼠在海马依赖性学习和记忆方面受损，并且大脑体积较小。最近，我们在衰老小鼠的海马 CA1 区描述了新的结构，这些结构显然源自退化的突触前末端，与同龄的 WT 小鼠相比，DPP6 敲除小鼠中更普遍存在这些结构，并且在 DPP6 敲除小鼠的发育过程中更早观察到这些结构。这些新结构表现为大斑点簇，与 NeuN、突触小泡蛋白和嗜铬粒蛋白 A 共定位，也部分标记为 MAP2、淀粉样β、APP、α-突触核蛋白和磷酸化 tau，突触素-1 和 VGluT1 标记在其外围。在本研究中，我们使用免疫荧光和电子显微镜证实 APP 和淀粉样β在这些结构中都很普遍；我们通过免疫荧光显示在阿尔茨海默病患者中存在类似的结构。在这里，我们还发现证据表明，衰老的 DPP6 突变体显示与阿尔茨海默病相关的其他变化。我们使用体内 MRI 显示 DPP6 敲除小鼠的大脑和海马体缩小。衰老的 DPP6-KO 海马体中神经元总数减少，神经元死亡增加，并且存在阿尔茨海默病的诊断生物标志物，包括淀粉样β和 APP 的积累以及过度磷酸化 tau 的表达增加。淀粉样β和磷酸化 tau 病理学与神经炎症有关，特征为小胶质细胞和星形胶质细胞的增加。衰老的 DPP6-KO 小鼠中的促炎或抗炎细胞因子水平增加。最后，我们表明衰老的 DPP6-KO 小鼠表现出昼夜节律功能障碍，这是阿尔茨海默病的常见症状。总之，这些结果表明，衰老的 DPP6-KO 小鼠表现出增强的神经退行性变症状，类似于与突触丢失和神经元死亡相关的新型结构引起的痴呆症。本研究延续了我们实验室对 DPP6 功能的研究，并提供了令人信服的证据表明 DPP6 在阿尔茨海默病中发挥直接作用。
