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. 2014 Jun 17:6:116.
doi: 10.3389/fnagi.2014.00116. eCollection 2014.

Deficits in the miRNA-34a-regulated endogenous TREM2 phagocytosis sensor-receptor in Alzheimer's disease (AD); an update

Surjyadipta Bhattacharjee  1 , Yuhai Zhao  1 , Walter J Lukiw  1
Affiliations

Deficits in the miRNA-34a-regulated endogenous TREM2 phagocytosis sensor-receptor in Alzheimer's disease (AD); an update

Surjyadipta Bhattacharjee et al. Front Aging Neurosci. .
No abstract available

Keywords: Alzheimer's disease; TREM2; amyloidosis; innate-immune response; miRNA-34a; phagocytosis.

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Figures

Figure 1
Figure 1
(A) Murine microglial cell mediated phagocytosis of Aβ42 peptides; 3 day old C8B4 murine microglia cells (ATCC CRL-2540; ATCC, Manassus VA) were treated with 5 μ M of Aβ42 for 24 h before staining; Aβ42 peptides (American Peptide Company, Sunnyvale, CA, cat # 62-0-80A) were prepared as described by Stine et al. (2003). Briefly, Aβ42 peptides were initially solubilized in hexafluoroisopropanol (HFIP; Fluka Chemical, cat# 52512; Sigma-Aldrich, St. Louis MO), aliquoted, and stored at −20°C as an HFIP film. After vacuum evaporation of HFIP, aliquoted peptide was re-suspended with DMSO to 5 mM and diluted to 5 μM into the cell culture media; cells were subsequently stained using a murine amyloid beta MABN10 (red fluorescence λmax ~650 nm; anti-Aβ antibody, clone W0-2; Millipore, Bellerica MA), a TREM-2 antibody (M-227): sc-48765 (green fluorescence; λmax ~510 nm; Santa Cruz, Santa Cruz CA) or DAPI nuclear stain; magnification 60×; note self-aggregation of Aβ42 peptide after 24 h and Aβ42 peptide affinity for TREM2 containing cells (leftmost panels) and internalization (rightmost panel; yellow merge; λmax ~580 nm); additional relevant methods have been described (Griciuc et al., ; Zhao and Lukiw, 2013); (B) highly schematicized depiction of the possible actions of an NF-kB-regulated, miRNA-34a-mediated TREM2 sensor-phagocytosis protein down-regulated in AD brain; the triggering receptor for myeloid/microglial cells (TREM2) is a variably glycosylated transmembrane receptor known to be enriched in the microglial cell plasma membrane; signaling via the tyrosine kinase-binding protein (DNAX activation protein 12) [TYROBP (DAP12)] accessory receptor results in phagocytosis and ultimately, clearance of Aβ42 peptides (red ovals) from the extracellular space (Satoh et al., ; Benitez et al., ; Forabosco et al., ; Hickman and Khoury, 2014); interestingly, TREM2 knockout/knockdown mice have attenuated immunological and inflammatory responses and/or increases in age-related neuroinflammatory markers and cognitive deficiency (Jiang et al., ; Sieber et al., 2013); TYROBP knockout mice exhibit immune system deficits and an impairment in microglial cell differentiation (Nataf et al., ; Sieber et al., 2013); it is not clear what, if any, contribution TREM2 makes directly to phagocytosis and Aβ42 clearance (question mark) without TYROBP (DAP12); while no deficits in TYROBP (DAP12) have been observed in sporadic AD brain, insufficient TREM2 may be in part responsible for the inability to adequately phagocytose Aβ42 peptides, resulting in their buildup and self-aggregation in the extracellular space. Inset: miRNA-34a is found to be significantly increased in AD hippocampal CA1 and superior temporal lobe and in stressed microglial cells; miRNA-34a targeting of the TREM2 mRNA 3′-UTR appears to be in part responsible for this (see text); because miRNA-34a is encoded on an NF-kB-sensitive transcript, both anti-NF-kB and/or anti-miRNA strategies may be clinically useful in the restoration of homeostatic phagocytosis in the brain and CNS.
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