Alzheimer's disease/dementia-associated brain pathology in aging DPP6-KO mice

海马结构 突触素 小胶质细胞 神经炎症 纽恩 海马体 突触蛋白I 阿尔茨海默病 促炎细胞因子 生物 二肽基肽酶 淀粉样蛋白(真菌学) 神经科学 病理 医学 免疫组织化学 生物化学 免疫学 炎症 疾病 突触小泡 小泡
作者
Lin Lin,Ronald S. Petralia,Lynne Holtzclaw,Ya-Xian Wang,Daniel Abebe,Dax A. Hoffman
出处
期刊:Neurobiology of Disease [Elsevier BV]
卷期号:: 105887-105887
标识
DOI:10.1016/j.nbd.2022.105887
摘要

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. • Aging DPP6-KO mice show reduced hippocampal volume as found in AD • Hyperphosphorylated tau and amyloid accumulate in aging DPP6-KO mice • APP accumulation in presynaptic terminals is associated with increased invaginations • Neuroinflammation with increased cytokines and astroglia/microglia in DPP6-KO • Similar novel NeuN-labeled structures are found in hippocampal CA1 of AD donors
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