Activated Cyclin-Dependent Kinase 5 Promotes Microglial Phagocytosis of Fibrillar β-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. Molecular & Cellular

TREM2 regulates microglial cell activation in response to demyelination in vivo

“…6b). LPL is an enzyme implicated in the degradation of lipids that is expressed in microglia in the CNS [19, 43]. We evaluated LPL expression by qRT-PCR in TREM2 −/− and WT microglia isolated from the brain of naïve TREM2 −/− and WT mice and at 4 weeks on CPZ .…”

“…However, we cannot conclude if the reduction of LPL is a downstream effect or a direct consequence of lack of TREM2. Interestingly, LPL accumulates in senile plaques of AD brains [55], and microglial LPL has been suggested to play a role in amyloid β uptake and degradation in vitro [43]. …”

Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress

“…However, although Lsp1 expression is lower in the Het samples at weeks 5 and 24, Lpl expression is higher in the Het samples at 5 weeks but lower at 24 weeks. Interestingly, reducing Lpl expression in BV2 microglia and primary microglial cells reduces microglial phagocytosis of fibrillar β-amyloid [53]. Correspondingly, reduced Lpl immunoreactivity has been found in granule cells of the dentate gyrus and the associated synaptic network in Alzheimer’s disease postmortem samples compared to control tissue [54].…”

Quantitative proteomics reveals that PEA15 regulates astroglial Aβ phagocytosis in an Alzheimer's disease mouse model

“…The Aβ plaques in the brain can activate both microglia and astrocytes, and the reactive glial cells play an important role in removing Aβ in the early stages of AD [3,[11][12][13][14][15]. Contrary to microglia, astrocytes can phagocytose and degrade Aβ in the absence of cytokine stimulation [16,17].…”