Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
J Neuroinflammation. 2022 Jan 6;19(1):5. doi: 10.1186/s12974-021-02369-8.
Neurodegeneration is considered the consequence of misfolded proteins' deposition. Little is known about external environmental effects on the neurodegenerative process. Infectious agent-derived pathogen-associated molecular patterns (PAMPs) activate microglia, key players in neurodegenerative diseases. We hypothesized that systemic microbial pathogens may accelerate neurodegeneration in Alzheimer's disease (AD) and that microglia play a central role in this process.
We examined the effect of an infectious environment and of microbial Toll-like receptor (TLR) agonists on cortical neuronal loss and on microglial phenotype in wild type versus 5xFAD transgenic mice, carrying mutated genes associated with familial AD.
We examined the effect of a naturally bred environment on the neurodegenerative process. Earlier and accelerated cortical neuron loss occurred in 5xFAD mice housed in a natural ("dirty") environment than in a specific-pathogen-free (SPF) environment, without increasing the burden of Amyloid deposits and microgliosis. Neuronal loss occurred in a microglia-rich cortical region but not in microglia-poor CA regions of the hippocampus. Environmental exposure had no effect on cortical neuron density in wild-type mice. To model the neurodegenerative process caused by the natural infectious environment, we injected systemically the bacterial endotoxin lipopolysaccharide (LPS), a TLR4 agonist PAMP. LPS caused cortical neuronal death in 5xFAD, but not wt mice. We used the selective retinoic acid receptor α agonist Am580 to regulate microglial activation. In primary microglia isolated from 5xFAD mice, Am580 markedly attenuated TLR agonists-induced iNOS expression, without canceling their basic immune response. Intracerebroventricular delivery of Am580 in 5xFAD mice reduced significantly the fraction of (neurotoxic) iNOS + microglia and increased the fraction of (neuroprotective) TREM2 + microglia. Furthermore, intracerebroventricular delivery of Am580 prevented neurodegeneration induced by microbial TLR agonists.
Exposure to systemic infections causes neurodegeneration in brain regions displaying amyloid pathology and high local microglia density. AD brains exhibit increased susceptibility to microbial PAMPs' neurotoxicity, which accelerates neuronal death. Microglial modulation protects the brain from microbial TLR agonist PAMP-induced neurodegeneration.
神经退行性变被认为是蛋白质错误折叠沉积的结果。关于外部环境对神经退行性过程的影响知之甚少。感染性病原体来源的病原体相关分子模式 (PAMP) 会激活小胶质细胞，小胶质细胞是神经退行性疾病的关键参与者。我们假设系统微生物病原体可能会加速阿尔茨海默病 (AD) 中的神经退行性变，并且小胶质细胞在这个过程中起核心作用。
我们研究了感染环境和微生物 Toll 样受体 (TLR) 激动剂对携带与家族性 AD 相关基因突变的 5xFAD 转基因小鼠皮质神经元丢失和小胶质细胞表型的影响。
我们研究了自然繁殖环境对神经退行性过程的影响。与在无特定病原体 (SPF) 环境中饲养的 5xFAD 小鼠相比，在自然（“肮脏”）环境中饲养的 5xFAD 小鼠出现了更早和加速的皮质神经元丢失，而不会增加淀粉样沉积和小胶质细胞增多的负担。神经元丢失发生在富含小胶质细胞的皮质区域，而不是富含小胶质细胞的海马 CA 区域。环境暴露对野生型小鼠的皮质神经元密度没有影响。为了模拟自然感染环境引起的神经退行性过程，我们系统注射了细菌内毒素脂多糖 (LPS)，一种 TLR4 激动剂 PAMP。LPS 导致 5xFAD 但不导致 wt 小鼠皮质神经元死亡。我们使用选择性维甲酸受体 α 激动剂 Am580 来调节小胶质细胞激活。从小胶质细胞中分离出的 5xFAD 小鼠的原代小胶质细胞中，Am580 显著抑制 TLR 激动剂诱导的 iNOS 表达，而不取消其基本免疫反应。在 5xFAD 小鼠的侧脑室给予 Am580 可显著减少（神经毒性）iNOS+小胶质细胞的比例，并增加（神经保护）TREM2+小胶质细胞的比例。此外，侧脑室给予 Am580 可预防微生物 TLR 激动剂诱导的神经退行性变。
全身感染会导致具有淀粉样病理学和局部小胶质细胞密度高的脑区发生神经退行性变。AD 大脑对微生物 PAMP 的神经毒性易感性增加，从而加速神经元死亡。小胶质细胞调节可保护大脑免受微生物 TLR 激动剂 PAMP 诱导的神经退行性变。
