Lau Victor Z, Awogbindin Ifeoluwa O, Frenkel Dan, Whitehead Shawn N, Tremblay Marie-Ève
Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
Institute on Aging and Lifelong Health (IALH), University of Victoria, Victoria, British Columbia, Canada.
Alzheimers Dement. 2025 Jun;21(6):e70363. doi: 10.1002/alz.70363.
Lewy body-involving diseases (LBD) are commonly associated with Parkinson's disease (PD) featuring voluntary movement inhibition, due to dopaminergic neuron dysfunction in the substantia nigra. PD is clinically tracked through Lewy bodies (LB), composed of insoluble α-synuclein aggregates sequestered with organelles, particularly inside neurons. However, α-synuclein pathology also appears in incidental LBD, Parkinson's disease dementia, and dementia with LB (DLB). Incomplete explanations address how these clinical pathologies interrelate, LBD etiology variability, and frequently overlapping α-synuclein and Alzheimer's disease (AD) pathologies. We hypothesize that (1) chronic environmental insult exposure and (2) senescence(-like) neuron accumulation contribute toward initiating and sustaining LBD; individual cell vulnerability determines either cell reactivity, death, or senescence in response to environmental insults. We predicate that parkinsonian and other neurodegenerative symptoms over LBD progression involve (3) co-occurring AD pathologies, wherein dementia symptomology develops when synergistic glial senescence, tau hyperphosphorylation, and possible α-synuclein aggregation reach into regions involved in AD progression. HIGHLIGHTS: Senescence burden is predicted to explain α-synucleinopathy progression. Senescence and cell death are hypothesized to occur in α-synucleinopathies. Sub-apoptotic stress is proposed to induce senescence in α-synucleinopathies. Neuronal senescence likely first spreads α-synucleinopathies to new regions. Glial senescence likely underlies Parkinson's disease and Alzheimer's disease overlap.
路易体相关疾病（LBD）通常与帕金森病（PD）相关，后者因黑质中多巴胺能神经元功能障碍而具有随意运动抑制的特征。PD在临床上通过路易体（LB）进行追踪，路易体由与细胞器隔离的不溶性α-突触核蛋白聚集体组成，特别是在神经元内部。然而，α-突触核蛋白病理学也出现在偶发性LBD、帕金森病痴呆和路易体痴呆（DLB）中。目前对于这些临床病理学如何相互关联、LBD病因的变异性以及α-突触核蛋白与阿尔茨海默病（AD）病理学频繁重叠的解释并不完整。我们假设：（1）长期暴露于环境损伤和（2）衰老样神经元积累有助于启动和维持LBD；个体细胞的易损性决定了细胞对环境损伤的反应是反应性、死亡还是衰老。我们推测，LBD进展过程中的帕金森病及其他神经退行性症状涉及（3）同时出现的AD病理学，其中当协同性胶质细胞衰老、tau蛋白过度磷酸化以及可能的α-突触核蛋白聚集累及AD进展相关区域时，痴呆症状就会出现。要点：预计衰老负担可解释α-突触核蛋白病的进展。假设衰老和细胞死亡发生在α-突触核蛋白病中。提出亚凋亡应激可诱导α-突触核蛋白病中的衰老。神经元衰老可能首先将α-突触核蛋白病传播到新的区域。胶质细胞衰老可能是帕金森病和阿尔茨海默病重叠的基础。
