Abstract
Loss of neuronal polarity and missorting of the axonal microtubule-associated-protein TAU are hallmarks of Alzheimer’s disease (AD) and related tauopathies. Impairment of mitochondrial function is causative for various mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is unclear. The axon-initial-segment (AIS) is vital for maintaining neuronal polarity, action potential generation, and—here important—TAU-sorting. Here, we investigate the role of mitochondria in the AIS for maintenance of TAU cellular polarity. Using not only global and local mitochondria impairment via inhibitors of the respiratory chain and a locally activatable protonophore/uncoupler, but also live-cell-imaging and photoconversion methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived forebrain/cortical neurons, and assessed somatic presence of TAU. Global application of mitochondrial toxins efficiently induced tauopathy-like TAU-missorting, indicating involvement of mitochondria in TAU-polarity. Mitochondria show a biased distribution within the AIS, with a proximal cluster and relative absence in the central AIS. The mitochondria of this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Locally constricted impairment of the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Mechanistically, mitochondrial impairment sufficient to induce TAU-missorting results in decreases of calcium oscillation but increases in baseline calcium, yet chelating intracellular calcium did not prevent mitochondrial impairment-induced TAU-missorting. Stabilizing microtubules via taxol prevented TAU-missorting, hinting towards a role for impaired microtubule dynamics in mitochondrial-dysfunction-induced TAU-missorting. We provide evidence that the mitochondrial distribution within the proximal axon is biased towards the proximal AIS and that proper function of this newly described mitochondrial cluster may be essential for the maintenance of TAU polarity. Mitochondrial impairment may be an upstream event in and therapeutic target for AD/tauopathy.
Highlights
Alzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders that impose a huge burden on the aging society [1]
In agreement with previous experiments showing that mitochondrial impairment leads to increased cytosolic calcium levels and our initial findings that TAU missorting in response to mitochondrial impairment occurs within hours (Figs. 1, 4c–e), we found that 50 nM Antimycin A (AMA) treatment of primary neurons resulted in slight elevation of baseline calcium levels over the time of 1 h when assayed via Fluo-4 live-imaging (Suppl. 3a–c), to roughly twofold of initial baseline levels
We investigated the relation of mitochondrialfunction and TAUsorting
Summary
Alzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders that impose a huge burden on the aging society [1]. Pathological hallmarks of these tauopathies are abnormal phosphorylation, subcellular mislocalization and eventually, aggregate formation (mainly neurofibrillary tangles) of the microtubule-associated protein TAU [2]. While the mechanisms of axonal TAU sorting are still under debate [3, 4], there is evidence for a major role of the axon initial segment (AIS) for mediation of axonal TAU targeting [5, 6]. The AIS is characterized by a highly structured cytoskeleton with enrichment of specific proteins (e.g. ANKRYIN-G, TRIM-46), very particular microtubule structures (highly structured fascicles) and dynamics (highly unstable microtubules, but high density and possibly EB3-mediated tethering to membranes) [5, 8,9,10] and voltage gated potassium/sodium channels [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
