Traumatic brain injury (TBI) increases the risk for dementias including Alzheimer's disease (AD) and chronic traumatic encephalopathy. Further, both human and animal model data indicate that amyloid-beta (Aβ) peptide accumulation and its production machinery are upregulated by TBI. Considering the clear link between chronic Aβ elevation and AD as well as tau pathology, the role(s) of Aβ in TBI is of high importance. Endopeptidases, including the neprilysin (NEP)-like enzymes, are key mediators of Aβ clearance and may affect susceptibility to pathology post-TBI. Here, we use a “humanized” mouse model of Aβ production, which expresses normal human amyloid-beta precursor protein (APP) under its natural transcriptional regulation and exposed them to a more clinically relevant repeated closed-head TBI paradigm. These transgenic mice also were crossed with mice deficient for the Aβ degrading enzymes NEP or NEP2 to assess models of reduced cerebral Aβ clearance in our TBI model. Our results show that the presence of the human form of Aβ did not exacerbate motor (Rotarod) and spatial learning/memory deficits (Morris water maze) post-injuries, while potentially reduced anxiety (Open Field) was observed. NEP and NEP2 deficiency also did not exacerbate these deficits post-injuries and was associated with protection from motor (NEP and NEP2) and spatial learning/memory deficits (NEP only). These data suggest that normally regulated expression of wild-type human APP/Aβ does not contribute to deficits acutely after TBI and may be protective at this stage of injury.

中文翻译：

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评估改变的β淀粉样蛋白清除对β淀粉样蛋白前体蛋白人源化小鼠重复闭头脑损伤后行为的影响

创伤性脑损伤 (TBI) 会增加痴呆症的风险，包括阿尔茨海默病 (AD) 和慢性创伤性脑病。此外，人类和动物模型数据都表明，β-淀粉样蛋白 (Aβ) 肽的积累及其生产机制被 TBI 上调。考虑到慢性 Aβ 升高与 AD 以及 tau 病理学之间的明确联系，Aβ 在 TBI 中的作用非常重要。内肽酶，包括中性溶酶 (NEP) 样酶，是 Aβ 清除的关键介质，可能会影响 TBI 后对病理的易感性。在这里，我们使用 Aβ 生产的“人源化”小鼠模型，该模型在其自然转录调控下表达正常的人类淀粉样蛋白-β 前体蛋白 (APP)，并将它们暴露于更临床相关的重复闭头 TBI 范例。这些转基因小鼠还与缺乏 Aβ 降解酶 NEP 或 NEP2 的小鼠杂交，以评估我们的 TBI 模型中脑 Aβ 清除率降低的模型。我们的研究结果表明，人类 Aβ 的存在并没有加剧受伤后的运动（Rotarod）和空间学习/记忆缺陷（Morris 水迷宫），同时观察到潜在的焦虑减少（开放场）。NEP 和 NEP2 缺乏也没有加剧这些损伤后的缺陷，并且与运动保护（NEP 和 NEP2）和空间学习/记忆缺陷（仅 NEP）有关。这些数据表明，正常调节的野生型人 APP/Aβ 表达不会导致 TBI 后的急性缺陷，并且可能在这一损伤阶段具有保护作用。