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Activated cyclin-dependent kinase 5 promotes microglial phagocytosis of fibrillar ?-amyloid by up-regulating lipoprotein lipase expression.

ABSTRACT: Amyloid plaques are crucial for the pathogenesis of Alzheimer disease (AD). Phagocytosis of fibrillar ?-amyloid (A?) by activated microglia is essential for A? clearance in Alzheimer disease. However, the mechanism underlying A? clearance in the microglia remains unclear. In this study, we performed stable isotope labeling of amino acids in cultured cells for quantitative proteomics analysis to determine the changes in protein expression in BV2 microglia treated with or without A?. Among 2742 proteins identified, six were significantly up-regulated and seven were down-regulated by A? treatment. Bioinformatic analysis revealed strong over-representation of membrane proteins, including lipoprotein lipase (LPL), among proteins regulated by the A? stimulus. We verified that LPL expression increased at both mRNA and protein levels in response to A? treatment in BV2 microglia and primary microglial cells. Silencing of LPL reduced microglial phagocytosis of A?, but did not affect degradation of internalized A?. Importantly, we found that enhanced cyclin-dependent kinase 5 (CDK5) activity by increasing p35-to-p25 conversion contributed to LPL up-regulation and promoted A? phagocytosis in microglia, whereas inhibition of CDK5 reduced LPL expression and A? internalization. Furthermore, A? plaques was increased with reducing p25 and LPL level in APP/PS1 mouse brains, suggesting that CDK5/p25 signaling plays a crucial role in microglial phagocytosis of A?. In summary, our findings reveal a potential role of the CDK5/p25-LPL signaling pathway in A? phagocytosis by microglia and provide a new insight into the molecular pathogenesis of Alzheimer disease.

SUBMITTER: Ma Y

PROVIDER: S-EPMC3790294 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Activated cyclin-dependent kinase 5 promotes microglial phagocytosis of fibrillar β-amyloid by up-regulating lipoprotein lipase expression.

Ma Yuanhui Y Bao Jintao J Zhao Xuyang X Shen Hongyan H Lv Junniao J Ma Shuaipeng S Zhang Xuefei X Li Zeyang Z Wang Shuxin S Wang Qingsong Q Ji Jianguo J

Molecular & cellular proteomics : MCP 20130701 10

Amyloid plaques are crucial for the pathogenesis of Alzheimer disease (AD). Phagocytosis of fibrillar β-amyloid (Aβ) by activated microglia is essential for Aβ clearance in Alzheimer disease. However, the mechanism underlying Aβ clearance in the microglia remains unclear. In this study, we performed stable isotope labeling of amino acids in cultured cells for quantitative proteomics analysis to determine the changes in protein expression in BV2 microglia treated with or without Aβ. Among 2742 pr ...[more]

PMID: 23816988

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Project description:BackgroundReactive microglia are associated with ?-amyloid (A?) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear A? deposits although they mainly exist in an "activated" state. Oligomeric A? (oA?), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar A? (fA?). However, the role of the different A? forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.ResultsWe demonstrated that A?(1-42) fibrils, not A?(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oA?(1-42) not only attenuated fA?(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fA?(1-42). Compared with the fA?(1-42) treatment, the oA?(1-42) treatment resulted in a rapid and transient increase in interleukin 1? (IL-1?) level and produced higher levels of tumor necrosis factor-? (TNF-?), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fA?(1-42)-induced microglia was decreased by IL-1?, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-?B (NF-?B) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oA?-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oA?(1-42) stimulation reduced the mRNA expression of CD36, integrin ?1 (Itgb1), and Ig receptor Fc?RIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oA?(1-42) or the inflammatory and oxidative milieu (IL-1?, LPS or t-BHP) significantly downregulated the fA?(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells.ConclusionThese results imply that A? oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of A? fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.

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Activated cyclin-dependent kinase 5 promotes microglial phagocytosis of fibrillar ?-amyloid by up-regulating lipoprotein lipase expression.

Publications

Activated cyclin-dependent kinase 5 promotes microglial phagocytosis of fibrillar β-amyloid by up-regulating lipoprotein lipase expression.

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