Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
J Neurotrauma. 2021 Mar;38(5):665-676. doi: 10.1089/neu.2020.6989. Epub 2021 Jan 8.
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.
创伤性脑损伤（TBI）增加了包括阿尔茨海默病（AD）和慢性创伤性脑病在内的痴呆症的风险。此外，人类和动物模型数据都表明，TBI 会上调淀粉样β（Aβ）肽的积累及其产生机制。鉴于慢性 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 Neprilysin（NEP）样酶，是 Aβ 清除的关键介质，并且可能会影响 TBI 后发生病理的易感性。在这里，我们使用 Aβ 产生的“人源化”小鼠模型，该模型在其天然转录调控下表达正常的人类淀粉样β前体蛋白（APP），并使其暴露于更具临床相关性的重复闭合性颅脑外伤（TBI）范式下。这些转基因小鼠还与缺乏 Aβ 降解酶 Neprilysin（NEP）或 Neprilysin2（NEP2）的小鼠杂交，以评估我们的 TBI 模型中降低脑内 Aβ 清除率的模型。我们的研究结果表明，人源 Aβ 的存在并没有加剧损伤后运动（转棒）和空间学习/记忆缺陷（Morris 水迷宫），而观察到潜在的焦虑减轻（旷场）。NEP 和 NEP2 缺乏也没有加剧损伤后的这些缺陷，并且与运动（NEP 和 NEP2）和空间学习/记忆缺陷（仅 NEP）的保护有关。这些数据表明，正常调节的野生型人 APP/Aβ 的表达不会导致 TBI 后急性缺陷，并且在损伤的这个阶段可能具有保护作用。
