Taddei Raquel N, Duff Karen E
Neurology Department, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
UK Dementia Research Institute at UCL, Institute of Neurology, University College London, London, UK.
Nat Rev Neurol. 2025 May 22. doi: 10.1038/s41582-025-01094-7.
Preservation of synapses is crucial for healthy cognitive ageing, and synapse loss is one of the closest anatomical correlates of cognitive decline in Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia. In these conditions, some synapses seem particularly vulnerable to degeneration whereas others are resilient and remain preserved. Evidence has highlighted that vulnerability and resilience are intrinsically distinct phenomena linked to specific brain structural and/or functional signatures, yet the key features of vulnerable and resilient synapses in the dementias remain incompletely understood. Defining the characteristics of vulnerable and resilient synapses in each form of dementia could offer novel insight into the mechanisms of synapse preservation and of synapse loss that underlies cognitive decline, thereby facilitating the discovery of targeted biomarkers and disease-modifying therapies. In this Review, we consider the concepts of synapse vulnerability and resilience, and provide an overview of our current understanding of the associations between synaptic protein changes, neuropathology and cognitive decline. We also consider how understanding of the underlying mechanisms could identify novel strategies to mitigate the cognitive dysfunction associated with dementias.
突触的保留对于健康的认知衰老至关重要，而突触丧失是阿尔茨海默病、路易体痴呆和额颞叶痴呆认知衰退最密切的解剖学相关因素之一。在这些情况下，一些突触似乎特别容易发生退化，而另一些则具有韧性并得以保留。有证据表明，脆弱性和韧性是与特定脑结构和/或功能特征相关的本质上不同的现象，但痴呆中脆弱和有韧性突触的关键特征仍未完全被理解。确定每种痴呆形式中脆弱和有韧性突触的特征，可能为认知衰退背后的突触保留和突触丧失机制提供新的见解，从而有助于发现靶向生物标志物和疾病修饰疗法。在本综述中，我们探讨了突触脆弱性和韧性的概念，并概述了我们目前对突触蛋白变化、神经病理学和认知衰退之间关联的理解。我们还考虑了对潜在机制的理解如何能够确定减轻与痴呆相关的认知功能障碍的新策略。
