Abstract
The accumulation of autophagosomes and dysfunction at the axonal terminal of neurons play crucial roles in the genesis and development of Alzheimer’s disease (AD). Abnormalities in neuron axonal transport-related proteins prevent autophagosome maturation in AD. Curcumin, a polyphenol plant compound, has been shown to exert neuroprotective effects by increasing autophagy in AD, but the underlying mechanism of its effect on autophagy axon transport remains elusive. This study investigated the effects of curcumin on autophagosome formation and axonal transport in N2a/APP695swe cells (AD cell model) as well as the mechanism underlying those effects. Curcumin treatment significantly increased the expression of Beclin1, Atg5, and Atg16L1, induced the formation of autophagosomes, and promoted autophagosome–lysosome fusion in N2a/APP695swe cells. At the same time, curcumin promoted the expression of dynein, dynactin, and BICD2 as well as their binding to form the retrograde axonal transport molecular motor complex. Moreover, curcumin also increased the expression of the scaffolding proteins Rab7- interacting lysosomal protein (RILP) and huntingtin in N2a/APP695swe cells. Taken together, our findings indicate that curcumin increases autophagic flux by promoting interactions among autophagic axonal transport-related proteins and inducing lysosome–autophagosome fusion. This study provides evidence suggesting the potential use of curcumin as a novel treatment for AD.
Highlights
Macroautophagy, commonly known as autophagy, is the process of intracellular self-degradation, whereby cellular components such as misfolded proteins and damaged organelles are systematically degraded and recycled [1]
The direction of transport entirely depends on the resultant force of forward and retrograde transport [10], which is affected by the type of molecular motor, scaffolding proteins (Huntingtin and Rab7- interacting lysosomal protein), and adaptor www.aging-us.com proteins (Bicaudal D, two-tailed D and dynactin) recruited [11,12,13,14,15,16]
TEM (Transmission electron microscopy) images revealed that autophagic structures were clearly present in the WT group, whereas few were observed in the N2a/APP695swe and DMSO groups (Figure 1A)
Summary
Macroautophagy, commonly known as autophagy, is the process of intracellular self-degradation, whereby cellular components such as misfolded proteins and damaged organelles are systematically degraded and recycled [1]. Autophagy is essential in post-mitotic neurons and occurs more frequently in dendrites and distal axons, which is important for maintaining cell stability [5,6,7]. Autophagosomes generated in distal axons can reach the cell body and bind to lysosomes through dynein-mediated retrograde axonal transport [8]. This dynamic process is called autophagic flux, and its integrity is essential for autophagy to progress [9]. Recent studies have shown that dynein, a key protein that mediates retrograde axonal transport, often forms complexes with dynactin (dynamic actin) [17], P150Glued [18], and BICD2 (Bicaudal D, two-tailed D) [16] to guide the retrograde transport of substances. Increasing autophagic activity and maintaining normal autophagic flux in neurodegenerative diseases has become a new focus of research and a therapeutic target
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