Amyloid-β Impairs Dendritic Trafficking of Golgi-Like Organelles in the Early Phase Preceding Neurite Atrophy: Rescue by Mirtazapine

Abstract

Neurite atrophy with loss of neuronal polarity is a pathological hallmark of Alzheimer’s disease (AD) and other neurological disorders. While there is substantial agreement that disruption of intracellular vesicle trafficking is associated with axonal pathology in AD, comparatively less is known regarding its role in dendritic atrophy. This is a significant gap of knowledge because, unlike axons, dendrites are endowed with the complete endomembrane system comprising endoplasmic reticulum (ER), ER–Golgi intermediate compartment (ERGIC), Golgi apparatus, post-Golgi vesicles, and a recycling-degradative route. In this study, using live-imaging of pGOLT-expressing vesicles, indicative of Golgi outposts and satellites, we investigate how amyloid-β (Aβ) oligomers affect the trafficking of Golgi-like organelles in the different dendritic compartments of cultured rat hippocampal neurons. We found that short-term (4 h) treatment with Aβ led to a decrease in anterograde trafficking of Golgi vesicles in dendrites of both resting and stimulated (with 50 mM KCl) neurons. We also characterized the ability of mirtazapine, a noradrenergic and specific serotonergic tetracyclic antidepressant (NaSSA), to rescue Golgi dynamics in dendrites. Mirtazapine treatment (10 μM) increased the number and both anterograde and retrograde motility, reducing the percentage of static Golgi vesicles. Finally, mirtazapine reverted the neurite atrophy induced by 24 h treatment with Aβ oligomers, suggesting that this drug is able to counteract the effects of Aβ by improving the dendritic trafficking of Golgi-related vesicles.

Cytotoxic Effect of Amyloid-β1-42 Oligomers on Endoplasmic Reticulum and Golgi Apparatus Arrangement in SH-SY5Y Neuroblastoma Cells

“…It has been demonstrated in brain tissue samples and experimental models of AD with Aβ that the abnormal rearrangement of the GA affects cell morphology and several physiological functions [97][98][99]. It had been reported that Aβ can alter the GA indirectly through the abnormal acetylation of cytoskeleton proteins, as well as by the induction of Tau hyperphosphorylation and cytoskeleton destabilization, which in turn disrupt intracellular transport [27,100,101]. Rodriguez-Cruz and collaborators recently reported similar data but using Tau protein overexpression as a pathological stimulus in SH-SY5Y cells.…”

“…To check if the AβOs obtained after 24 h of oligomerization could induce cytotoxicity in SH-SY5Y cells, as many reports suggest [23][24][25], we analyzed the cell viability 3, 12, 24, 48, 72, and 96 h after exposure to 10 µM AβOs, a concentration previously determined by other authors [26][27][28]. At the end of the exposure time, we used the MTT reduction assay to evaluate cell viability.…”

Cell Model of Depression: Reduction of Cell Stress with Mirtazapine

“…Furthermore, it is known that this antidepressant drug acts on the gene expressions of pro-apoptotic (Bax and p53) proteins, reducing their expressions [11]. With the application of this drug, there is also evidence of reduced neurite atrophy, a phenomenon that is evidenced in depression [25][26][27]. By establishing a stress model that is similar to the oxidative stress that occurs in individuals with depression, the doors were opened to the studying of other compounds that may be able to reverse or attenuate this damage.…”

Comparison of Protective Effects of Antidepressants Mediated by Serotonin Receptor in Aβ-Oligomer-Induced Neurotoxicity

“…In a study using human neuroblastoma cells, Flx was found to reduce intracellular Aβo concentration [ 15 ]. In contrast, mouse model studies on AD have shown that Flx can lower Aβ levels in brain tissue, cerebrospinal fluid, and serum, delaying cognitive decline [ 16 , 17 ]. Additionally, Mir has been reported to reverse neurite atrophy caused by Aβo [ 18 ], and Flx and Dlx have demonstrated antioxidant effects in animal brain tissue [ 19 , 20 ].…”