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. 2025 May 1;20(5):1407-1408.
doi: 10.4103/NRR.NRR-D-24-00253. Epub 2024 Jun 3.

Amyloid-β-induced disruption of axon-initial-segment mitochondria localization: consequences for TAU missorting in Alzheimer's disease pathology

Daniel Adam  1   2 , Felix Langerscheidt  1   2 , Hans Zempel  1   2
Affiliations

Amyloid-β-induced disruption of axon-initial-segment mitochondria localization: consequences for TAU missorting in Alzheimer's disease pathology

Daniel Adam et al. Neural Regen Res. .
No abstract available

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Figures

Figure 1
Figure 1
Amyloid-β insult induces mitochondria displacement into the central AIS. (A) Overview image of untreated rat hippocampal neurons stained for ANKG (red), as an AIS marker, and MAP2 (blue) as a dendritic marker. cb = cell body, arrowheads mark AIS. (B) Rat hippocampal neurons (21 DIV) were stained for MAP2 (blue), ANKG (red), and mitochondria (green). Cells were vehicle-treated (top, ctrl) or treated with 1 µM AβO for 30 minutes (bottom). Left: image showing the proximal AIS (boxed area) and the cell body (cb). Right: Magnification of boxed area. (Proximal) axons are indicated by dotted lines, arrowheads point to the void space of the AIS in control conditions, and to mitochondrial invasion of the AIS after treatment. Scale bar: 2 µm. (C) Quantification of B, the relative change of mitochondrial fluorescence intensity within the AIS after Aβ insult for up to 3 hours. Changes are detected in independent cultures at time points 0, 5, 15, 30, 60, and 180 minutes after fixation of AβO-treated cultures. Central AIS: red, proximal AIS, grey. Mitochondria invade the AIS minutes after insult. Error bars show SEM. N = 2, n = 10. (D) Rat hippocampal neurons (16 DIV) were transfected with mitoRFP for 5 days, treated with 1 µM AβO, and imaged via time-lapse imaging. The axon is shown at 4, 10, 17, and 31 minutes (left to right). Dotted lines indicate the axon, arrowheads indicate the central AIS, cb = cell body, scale bar corresponds to 5 µm. Areas in red boxes are magnified 1.7 times. Note that mitochondria invade the AIS minutes after insult, but show also rapid reorganization starting within half an hour. (E) Proposed mechanism: AD-like stress results in cofilin/ADF-based F-actin disassembly, mitochondrial displacement into the AIS, and aberrant restructuring of F-actin. Healthy neurons exhibit organized/structured AIS, containing regular Ankyrin G (orange) and actin rings (purple), and AMC (i.e. mitochondria are excluded from the central AIS) and the TAU diffusion barrier (TDB) is intact, TAU (red) is sorted into the axon and largely excluded from the AIS and the cell body. After Aβ insult, the cofilin/Actin depolymerizing factor (ADF, blue) is activated via dephosphorylation at S203 and cleaves essential F-actin structures at the AIS. This loss of F-actin leads to destabilization of the AIS, as can be seen, e.g. by loss of Ankyrin G. The AMC destabilizes and mitochondria translocate to the central AIS. After aberrant activation of cofilin and loss of F-actin structures at the AIS, F-actin may be aberrantly regenerated within the AIS, leading to loss of the TAU diffusion barrier and pathological TAU missorting, a hallmark of AD. Unpublished data. Artworks have been designed with Microsoft PowerPoint. AbO: Amyloid-beta oligomers; AD: Alzheimer’s disease; ADF: actin depolymerization factor (cofilin); AIS: axon inital segment; AMC: AIS-located mitochondria cluster; ANKG: ankyrin G; CB: cell body; ctrl: control; DIV: days in vitro; MAP2: microtubule-associated protein 2; SEM: standard error of the mean; TDB: TAU diffusion barrier; WT: wildtype.
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