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A substantial body of evidence indicates that protein kinase C (PKC) is involved in the α-secretory processing of the amyloid precursor protein (APP), an event that reduces the formation of the pathogenic amyloid-β peptide. Recently, we have shown that trafficking and processing of APP are both impaired by knockdown of myosin II-B, one of the major neuronal motor proteins. Here, we provide evidence that the α-secretory processing of APP is mediated by PKC-dependent phosphorylation of myosin II-B. This signaling pathway provides an important link between APP and the neuronal cytoskeleton and might be crucial for the understanding of the biological and pathological roles of APP. [ABSTRACT FROM AUTHOR]

The Alzheimer's disease (AD) brain pathology is characterized by extracellular deposits of amyloid-β (Aβ) peptides and intraneuronal fibrillar structures. These pathological features may be functionally linked, but the mechanism by which Aβ accumulation relates to neuronal degeneration is still poorly understood. Aβ peptides are fragments cleaved from the amyloid precursor protein (APP), a type I transmembrane protein ubiquitously expressed in the nervous system. Although the proteolytic processing of APP has been implicated in the pathogenesis of AD, the normal function of APP, whether this function is related to the proteolytic processing, and where this processing takes place in neurons remain unknown. APP is anterogradely transported along the axon apparently on cytoskeletal tracks. Moreover, several studies indicate that APP processing may occur within axonal or presinaptic terminals, supporting the hypothesis that APP functions as a vesicular receptor for cytoskeletal motor proteins. In the current study, we test the hypothesis that myosin 11, important contributor to the cytoskeleton of neuronal cells, may influence the trafficking and/or the processing of APP. Our results demonstrate that down-regulation of myosin II-B, the major myosin isoform in neurons, is able to increase Aβ secretion, concomitantly altering the subcellular localization of APP. These new insights might be important for the understanding of the function of APP and provide a novel conceptual framework in which to analyze its pathological role. [ABSTRACT FROM AUTHOR]

The Alzheimer's disease (AD) brain pathology is characterized by extracellular deposits of amyloid-β (Aβ) peptides cleaved from the amyloid precursor protein (APP). Although the proteolytic processing of APP has been implicated in the pathogenesis of AD, why and where this processing takes place in neurons remains unknown. Several studies support the hypothesis that APP functions as a vesicular receptor for cytoskeletal motor proteins. Our recent results strongly suggest that the trafficking of APP involves myosin II-B, important contributor to the cytoskeleton of neuronal cells (Massone et al., Biochem Biophys Res Commun. 2007 vol. 362 pp. 633-8). It is known that activation of protein kinase C (PKC) reduces secretion of Aβ favoring the non-amyloidogenic processing of APP. PKC phosphorylates myosin II-B, regulating the assembly of the motor protein and its shuttling between the cell cortex and the cytoplasm. These observations, together with our very recent results, are consistent with a model in which PKC-mediated phosphorylation of myosin II-B regulates shuttling of APP between the cell periphery and the perinuclear region, shifting APP away from the compartments where its amyloidogenic processing is favored or, alternatively, moving APP toward a non-amyloidogenic pathway. Work funded by Fondazione CARIGE (2007.0650-71) and PRIN (2006065711_002). [ABSTRACT FROM AUTHOR]

The treatment of THP-1 monocytes by ritonavir inhibits proteasome activity and increases CD36 scavenger receptor expression, events that are normalized by a-tocopherol co-treatment. Since a-tocopherol can reduce oxidative stress it appeared possible that normalization occurred by scavenging free radicals produced by proteasome inhibition. Alternatively, α-tocopherol may interfere with the ability of ritonavir to inhibit the proteasome. Indeed, in THP-1 monocytes, cellular proteasome inhibition by ritonavir or ALLN is associated with the production of oxidative stress. Both, ritonavir and ALLN produced similar amounts of oxidative stress; however, normalization of oxidative stress by α-tocopherol occurred only after inhibition by ritonavir and not by ALLN. Similar to that, α-tocopherol could normalize the reduced formation of 3-nitrotyrosine-modified proteins only after ritonavir treatment. In the absence of any proteasome inhibitor, intrinsic cellular proteasome activity was not modulated by α-, β-, and γ-tocopherols; however, δ-tocopherol, α-tocotrienol, and α-tocopheryl phosphate could significantly inhibit cellular proteasome activity and increased the level of p27Kip1 and p53. Since oxidative stress was only reduced by α-tocopherol after proteasome inhibition by ritonavir and not by ALLN, it is concluded that in this experimental system, α-tocopherol acts not as an antioxidant but interferes with proteasome inhibition by ritonavir. [ABSTRACT FROM AUTHOR]