Apoptosis, programmed cell death type I, is a critical part of neurodegeneration in cerebral ischemia, Parkinson’s, and Alzheimer’s disease. Apoptosis begins with activation of pro-death proteins Bax and Bak, release of cytochrome c and activation of caspases, loss of membrane integrity of intracellular organelles, and ultimately cell death. Approaches that block apoptotic pathways may prevent or delay neurodegenerative processes. Carotenoids are a group of pigments found in fruits, vegetables, and seaweeds that possess antioxidant properties. Over the last several decades, an increasing number of studies have demonstrated a protective role of carotenoids in neurodegenerative disease. In this review, we describe functions of commonly consumed carotenoids including lycopene, β-carotene, lutein, astaxanthin, and fucoxanthin and their roles in neurodegenerative disease models. We also discuss the underlying cellular mechanisms of carotenoid-mediated neuroprotection, including their antioxidant properties, role as signaling molecules, and as gene regulators that alleviate apoptosis-associated brain cell death.

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Objectives B-cell lymphoma-extra large (Bcl-xL) is a pro-survival protein localized to mitochondria and is also reported to support brain function by enhancing neuronal energy metabolism and synapse formation. We have previously shown that Bcl-xL is required for neurite outgrowth, and neurons lacking Bcl-xL were susceptible against neurotoxic challenges. In this study, we hypothesized that Bcl-xL supports maintaining neurite ATP by regulating mitochondrial motility. We thus tested if Bcl-xL depletion altered normal mitochondrial dynamics, neuronal energy retention, and neurite morphology. Methods Primary hippocampal neurons were transduced with either Bcl-xL shRNA or scrambled shRNA for 3 weeks. Mitochondria were labeled using mito-RFP BacMam2.0 and image sequences were obtained. Mitochondria motility parameters were quantified using KymoAnalyzer. Local ATP/ADP ratio was analyzed applying PercevalHR fluorescence biosensor, and neurite branches were quantified using Sholl analysis. We further tested viability of neurons against excitotoxicity applying calcein and propioduim iodin staining. Results Primary hippocampal neurons transduced with Bcl-xL shRNA decreased antero- and retrograde movement of mitochondria, lowered ATP/ADP ratio in neurites, and decreased length of neurites and number of branching points. Failure of achieving neurite complexity increased susceptibility of neurons to glutamate-induced excitotoxicity. Conclusions Primary hippocampal neurons transduced with Bcl-xL shRNA decreased antero- and retrograde movement of mitochondria, lowered ATP/ADP ratio in neurites, and decreased length of neurites and number of branching points. Failure of achieving neurite complexity increased susceptibility of neurons to glutamate-induced excitotoxicity. Funding Sources RGC Program (University of Alabama) Crenshaw Research Fund (University of Alabama) Sigma Xi Grants in Aid of Research (The National Academy of Sciences).

B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial protein known to inhibit mitochondria-dependent intrinsic apoptotic pathways. An increasing number of studies have demonstrated that Bcl-xL is critical in regulating neuronal energy metabolism and has a protective role in pathologies associated with an energy deficit. However, it is less known how Bcl-xL regulates physiological processes of the brain. In this study, we hypothesize that Bcl-xL is required for neurite branching and maturation during neuronal development by improving local energy metabolism. We found that the absence of Bcl-xL in rat primary hippocampal neurons resulted in mitochondrial dysfunction. Specifically, the ATP/ADP ratio was significantly decreased in the neurites of Bcl-xL depleted neurons. We further found that neurons transduced with Bcl-xL shRNA or neurons treated with ABT-263, a pharmacological inhibitor of Bcl-xL, showed impaired mitochondrial motility. Neurons lacking Bcl-xL had significantly decreased anterograde and retrograde movement of mitochondria and an increased stationary mitochondrial population when Bcl-xL was depleted by either means. These mitochondrial defects, including loss of ATP, impaired normal neurite development. Neurons lacking Bcl-xL showed significantly decreased neurite arborization, growth and complexity. Bcl-xL depleted neurons also showed impaired synapse formation. These neurons showed increased intracellular calcium concentration and were more susceptible to excitotoxic challenge. Bcl-xL may support positioning of mitochondria at metabolically demanding regions of neurites like branching points. Our findings suggest a role for Bcl-xL in physiological regulation of neuronal growth and development.