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1.  Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease 
ASN NEURO  2010;2(3):e00037.
Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred co-incident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4+ T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo, Tmem176b+ cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2+ microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2+ microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies.
PMCID: PMC2905103  PMID: 20640189
antigen presentation; autoimmunity; Clast1; neuroinflammation; Torid; Aβ, amyloid β peptide; CCL2, chemokine ligand 2; CFSE, carboxyfluorescein succinimidyl ester; CNS, central nervous system; DAMP, danger-associated molecular pattern; DMEM, Dulbecco's modified Eagle's medium; EAE, experimentally induced autoimmune encephalomyelitis; FBS, fetal bovine serum; GFP, green fluorescent protein; HPRT, hypoxanthine phosphoribosyl transferase; IFNγ, interferon γ; IL, interleukin; KO, knockout; LPS, lipopolysaccharide; PFA, paraformaldehyde; qPCR, quantitative PCR; Thio-S, thioflavine-S; Tmem176b, transmembrane domain protein 176b; TNF, tumour necrosis factor; TREM2, triggering receptor expressed on myeloid cells 2; WT, wild-type
2.  Memory deficits in APP23/Abca1+/− mice correlate with the level of Aβ oligomers 
ASN NEURO  2009;1(2):e00006.
ABCA1, a member of the ATP-binding cassette family of transporters, lipidates ApoE (apolipoprotein A) and is essential for the generation of HDL (high-density lipoprotein)-like particles in the CNS (central nervous system). Lack of Abca1 increases amyloid deposition in several AD (Alzheimer's disease) mouse models. We hypothesized that deletion of only one copy of Abca1 in APP23 (where APP is amyloid precursor protein) AD model mice will aggravate memory deficits in these mice. Using the Morris Water Maze, we demonstrate that 2-year-old Abca1 heterozygous APP23 mice (referred to as APP23/het) have impaired learning during acquisition, and impaired memory retention during the probe trial when compared with age-matched wild-type mice (referred to as APP23/wt). As in our previous studies, the levels of ApoE in APP23/het mice were decreased, but the differences in the levels of Aβ and thioflavin-S-positive plaques between both groups were insignificant. Importantly, dot blot analysis demonstrated that APP23/het mice have a significantly higher level of soluble A11-positive Aβ (amyloid β protein) oligomers compared with APP23/wt which correlated negatively with cognitive performance. To confirm this finding, we performed immunohistochemistry with the A11 antibody, which revealed a significant increase of A11-positive oligomer structures in the CA1 region of hippocampi of APP23/het. This characteristic region-specific pattern of A11 staining was age-dependent and was missing in younger APP23 mice lacking Abca1. In contrast, the levels of Aβ*56, as well as other low-molecular-mass Aβ oligomers, were unchanged among the groups. Overall, the results of the present study demonstrate that in aged APP23 mice memory deficits depend on Abca1 and are likely to be mediated by the amount of Aβ oligomers deposited in the hippocampus.
PMCID: PMC2695585  PMID: 19570031
ABCA1; Abca1-knockout mouse; Alzheimer's disease; amyloid β protein; apolipoprotein E (ApoE); APP transgenic mouse; Aβ, amyloid β protein; ABCA1, ATP-binding cassette transporter 1; AD, Alzheimer's disease; ApoE, apolipoprotein E; APP, amyloid precursor protein; CNS, central nervous system; DAPI, 4′,6-diamidino-2-phenylindole; GFAP, glial fibrillary acidic protein; HDL, high-density lipoprotein; LXR, liver X receptor; MWM, Morris Water Maze; PBST, PBS containing 0.2% Triton X-100; Thio-S, thioflavin S; X-34, 1,4-bis(3-carboxy-4-hydroxyphenylethenyl)-benzene

Results 1-2 (2)