Medical Record Room, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China.
Eur Rev Med Pharmacol Sci. 2020 Sep;24(18):9601-9614. doi: 10.26355/eurrev_202009_23048.
Vascular dementia is the second-most cause of dementia, characterized by cerebral infarcts, white matter lesions, myelin loss and often amyloid angiopathy. Hence, vascular damage is a critical cause of neuronal loss and synaptic disintegration. Abnormal neuroinflammation, autophagy and apoptosis are the prerequisite factors for endothelial and neuronal cell damage. This leads to the onset and progression of cerebrovascular disorders and cognitive dysfunction. The innate immune cells, pattern recognition receptors, Toll-like receptor-4 and related inflammatory mechanisms disrupt cerebrovascular integrity via glial activation and increased pro-inflammatory interleukins and TNFα. Inflammasome polymorphisms and multi-faceted neuro-immune interactions further integrate systemic and central inflammatory pathways, which induce vascular tissue injury and neurodegeneration. Specifically, chronic cerebral hypoperfusion disrupts the self-cannibalization mechanism of autophagy via altered expression of autophagy-specific proteins, Beclin-1, LC3 and P62. The deregulated autophagy pathway causes neuronal loss, hippocampal shrinkage, and ultimate loss in synaptic plasticity. The vascular dementia models typically exhibit downregulated anti-apoptotic Bcl-2 and upregulated pro-apoptotic Bax, cleaved caspase-3, and cleaved-PARP levels in the brain, for which modulated p38 MAPK and JNK phosphorylation pathways play a vital role. Endoplasmic stress-induced apoptosis, calcium overload and glutamate excitotoxicity in combination with ASK1-MAPK signaling mechanism also contribute to the cerebrovascular pathology. Vascular injury reduces neurological scores and increases the infarct volume, DNA damage and neuronal apoptosis in ischemia/reperfusion injury. Additionally, synergistic and additive interactions between inflammasome, autophagy and apoptotic signaling pathways augment symptoms of vascular neurodegeneration. Overall, the current review enlightens the key risk factors and underlying mechanism triggering vascular dementia. The review additionally informs the challenges associated while treating vascular dysfunction, and highlights the need for targeted drugs for reducing cerebrovascular damage.
血管性痴呆是痴呆的第二大病因，其特征是脑梗死、白质病变、髓鞘丢失，常伴有淀粉样血管病。因此，血管损伤是神经元丢失和突触解体的关键原因。异常的神经炎症、自噬和细胞凋亡是内皮细胞和神经元损伤的前提因素。这导致了脑血管疾病和认知功能障碍的发生和进展。先天免疫细胞、模式识别受体、Toll 样受体 4 及其相关炎症机制通过胶质细胞激活和增加促炎细胞因子和 TNFα 破坏脑血管完整性。炎性小体多态性和多方面的神经免疫相互作用进一步整合了全身和中枢炎症途径，诱导血管组织损伤和神经退行性变。具体来说，慢性脑灌注不足通过改变自噬特异性蛋白 Beclin-1、LC3 和 P62 的表达，破坏自噬的自我吞噬机制。失调的自噬途径导致神经元丢失、海马体萎缩和最终丧失突触可塑性。血管性痴呆模型通常表现为大脑中下调的抗凋亡 Bcl-2 和上调的促凋亡 Bax、裂解的 caspase-3 和裂解的 PARP 水平，其中调节的 p38 MAPK 和 JNK 磷酸化途径起着至关重要的作用。内质网应激诱导的细胞凋亡、钙超载和谷氨酸兴奋性毒性与 ASK1-MAPK 信号机制一起导致脑血管病变。血管损伤降低神经评分，增加缺血/再灌注损伤中的梗死体积、DNA 损伤和神经元凋亡。此外，炎性小体、自噬和凋亡信号通路的协同和累加相互作用加剧了血管性神经退行性变的症状。总的来说，本综述阐明了引发血管性痴呆的关键风险因素和潜在机制。该综述还介绍了治疗血管功能障碍相关的挑战，并强调了需要靶向药物来减少脑血管损伤的必要性。
