Insulin stimulates atypical protein kinase C‐mediated phosphorylation of the neuronal adaptor <scp>FE65</scp> to potentiate neurite outgrowth by activating <scp>ARF6‐Rac1</scp> signaling

Chau, Dennis Dik‐Long; Li, Wen; Chan, Wai Wa Ray; Sun, Jacquelyne Ka‐Li; Zhai, Yuqi; Chow, Hei Man; Lau, Kwok‐Fai

doi:10.1096/fj.202200757r

Cited by 3 publications

(2 citation statements)

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“…S1a–c ). Intriguingly, Fe65 has also been implicated in different functions such as insulin based potentiation of neurite outgrowth, 43 , 44 which could be further analyzed in the context of AD therapeutics. It is worth noting that Fe65-EXO could efficiently bind or be internalized by neuronal cells with APP overexpressed at a high magnitude, suggesting a capacity of Fe65-EXO to target APP overexpressed neuronal cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease

Iyaswamy,

Thakur,

Guan

et al. 2023

Sig Transduct Target Ther

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles in the brain. The overexpression of amyloid-β precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of amyloid-β and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD. Recently, exosome, a type of extracellular vesicle with diameter around 30–200 nm, has gained much attention as a potential delivery tool for brain diseases, including AD, due to their ability to cross the blood–brain barrier, their efficient uptake by autologous cells, and their ability to be surface-modified with target-specific receptor ligands. Here, the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65, enabled the development of a novel exosome-based targeted drug delivery system, which carried Corynoxine-B (Cory-B, an autophagy inducer) to the APP overexpressed-neuron cells in the brain of AD mice. The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes (Fe65-EXO) loaded with Cory-B (Fe65-EXO-Cory-B) hijacked the signaling and blocked the natural interaction between Fe65 and APP, enabling APP-targeted delivery of Cory-B. Notably, Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells, leading to amelioration of the cognitive decline and pathogenesis in AD mice, demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.

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Section: Discussionmentioning

confidence: 99%

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease

Iyaswamy,

Thakur,

Guan

et al. 2023

Sig Transduct Target Ther

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“…Although the mechanism has not been fully explored, it is generally achieved by insulin-activating Ras-related C3 botulinum toxin substrate 1 (Rac1). Rac1 is a small GTP enzyme associated with axonal growth ( 49 ). It can be observed that the PKC pathway involves multiple molecular pathways, and how to selectively utilize the PKC pathway is the problem we are facing.…”

Section: Mechanismmentioning

confidence: 99%

Diabetic peripheral neuropathy: pathogenetic mechanisms and treatment

Zhu,

Hu,

Luo

et al. 2024

Front. Endocrinol.

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Diabetic peripheral neuropathy (DPN) refers to the development of peripheral nerve dysfunction in patients with diabetes when other causes are excluded. Diabetic distal symmetric polyneuropathy (DSPN) is the most representative form of DPN. As one of the most common complications of diabetes, its prevalence increases with the duration of diabetes. 10-15% of newly diagnosed T2DM patients have DSPN, and the prevalence can exceed 50% in patients with diabetes for more than 10 years. Bilateral limb pain, numbness, and paresthesia are the most common clinical manifestations in patients with DPN, and in severe cases, foot ulcers can occur, even leading to amputation. The etiology and pathogenesis of diabetic neuropathy are not yet completely clarified, but hyperglycemia, disorders of lipid metabolism, and abnormalities in insulin signaling pathways are currently considered to be the initiating factors for a range of pathophysiological changes in DPN. In the presence of abnormal metabolic factors, the normal structure and function of the entire peripheral nervous system are disrupted, including myelinated and unmyelinated nerve axons, perikaryon, neurovascular, and glial cells. In addition, abnormalities in the insulin signaling pathway will inhibit neural axon repair and promote apoptosis of damaged cells. Here, we will discuss recent advances in the study of DPN mechanisms, including oxidative stress pathways, mechanisms of microvascular damage, mechanisms of damage to insulin receptor signaling pathways, and other potential mechanisms associated with neuroinflammation, mitochondrial dysfunction, and cellular oxidative damage. Identifying the contributions from each pathway to neuropathy and the associations between them may help us to further explore more targeted screening and treatment interventions.

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Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair

Revol,

Koistinen,

Menon

et al. 2023

Molecular and Cellular Neuroscience

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Insulin stimulates atypical protein kinase C‐mediated phosphorylation of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating ARF6‐Rac1 signaling

Cited by 3 publications

References 84 publications

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer’s disease

Diabetic peripheral neuropathy: pathogenetic mechanisms and treatment

Alpha-secretase dependent nuclear localization of the amyloid-β precursor protein-binding protein Fe65 promotes DNA repair

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