中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (5): 1407-1408.doi: 10.4103/NRR.NRR-D-24-00253

• 观点:退行性病与再生 • 上一篇    下一篇

β诱导的轴突起始段线粒体定位的破坏:阿尔茨海默病病理中TAU畸变的后果

  

  • 出版日期:2025-05-15 发布日期:2024-10-30

Aβ-induced disruption of axon-initial-segment mitochondria localization: consequences for TAU missorting in Alzheimer’s disease pathology

Daniel Adam, Felix Langerscheidt, Hans Zempel *   

  1. Instttute of Human Genettcs, University Hospital Cologne, Cologne, Germany (Adam D, Langerscheidt F, Zempel H)  Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany (Adam D, Langerscheidt F, Zempel H)
  • Online:2025-05-15 Published:2024-10-30
  • Contact: Hans Zempel, PhD, hans.zempel@uk-koeln.de.

摘要: https://orcid.org/0000-0002-7510-3077 (Hans Zempel) https://orcid.org/0009-0003-7983-8091 (Daniel Adam)

Abstract: TAU is a neuronal microtubule-associated protein preferentially located in axons. In a battery of neurodegenerattve diseases termed “tauopathies,” including Alzheimer’s disease (AD), TAU is missorted and abnormally phosphorylated, leading to fflamentous accumulattons of hyperphosphorylated TAU, a pathological hallmark and potenttal disease driver of AD and related tauopathies (Zempel, 2024). The other hallmark of AD is the aberrant production of amyloid-β (Aβ), which accumulates in extracellular plaques. The axon initial segment (AIS) is a 20 to 60 µM long neuronal compartment separattng the axon from the axon hillock and cell body. Its molecular organization is characterized by a complex protein scaffold, consisting of transmembrane proteins, Ankyrin G (ANKG), spectrins, acttn structures (rings/patches composed of filamentous actin (F-actin), microtubules, and microtubule-associated proteins (Leterrier, 2018). Alterations of the AIS structure have been observed as a result of Aβ exposure: F-acttn is lost at the AIS after exposure to amyloid-β-oligomers (AβO; AD-like stress), likely due to aberrant activation of the F-actin severing enzyme cofilin (actin depolymerizing factor). Subsequent rapid remodeling and repolarization of F-actin might induce TAU missorttng by blocking the physiological anterograde sorting of TAU into the axon (Zempel et al., 2017, Bell-Simons et al., 2023, Buchholz and Zempel, 2024). Recently, we also provided evidence for a cluster of mitochondria in the proximal AIS, which has a functional role in the maintenance of TAU sorting: While mitochondria show relative absence in the central AIS, they cluster at the proximal AIS. The mitochondria in this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Importantly, (local) impairment of this AIS-mitochondria-cluster (AMC) leads to detectable increases of somatic TAU, resembling AD-like TAU missorting (Tjiang and Zempel, 2022). While it is thus clear that both proper maintenance of F-acttn in the AIS, as well as proper functton of AIS-based mitochondria, may be crucial for neuronal function and maintenance of TAU sorttng and functton, the effect of AD-like stress on mitochondria in the AIS is underexplored.