Microglial networks in alzheimer’s disease
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Transcript of Microglial networks in alzheimer’s disease
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Microglial Networks in Alzheimer’s disease
John Hardy [email protected]
UCL Institute of Neurology United Kingdom
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Risk Loci for Alzheimer’s Disease (~6000
Samples: General Lessons hold true as Sample numbers increase)
BIN1, bridging integrator 1; OR, odds ratio.
Harold D, et al. Nat Genet. 2009;41:1088-1093; Hollingworth P, et al. Nat Genet. 2011;43:429-435; Lambert JC, et al. Nat Genet.
2009;41:1094-1099.
Apolipoprotein E4 OR ~4 Cholesterol metabolism: coding and expression
CLU OR ~1.4 Cholesterol metabolism: complement cascade—not coding, not simple expression
PICALM OR ~1.4 Endosomal vesicle recycling? Not coding
ABCA7 OR ~1.3 Cholesterol metabolism: not known but Gly1527Ala is possible
CR1 OR ~1.4 Complement cascade: very complicated—probably sequence and expression
BIN1 OR ~1.2 Endosomal vesicle recycling? Not coding
MS4AE OR ~1.2 Cell surface protein: not coding
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Normal Functioning CR1 and TREM2 Promote Neuroprotection by Microglia
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Loss of Function of CR1 and TREM2 Promotes Inflammation and Neurotoxicity
TNFa, tumor necrosis factor alpha.
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An introduction to the UK Brain Expression Consortium (UKBEC) data set
Frontal cortex (n=83)
Temporal cortex (n=72)
Occipital cortex (n=77)
Hippocampus (n=86)
Intralobular white matter (n=83)
Cerebellar cortex (n=76)
Thalamus (n=81)
Putamen (n=77)
Substantia nigra (n=65)
Medulla (inf. olivary nuc, n=88)
GENOME-WIDE EXPRESSION
From EACH brain sample 10 brain regions
Affy Human Exon 1.0 ST
arrays
CONTROL HUMAN BRAINS N = 134
ONLY samples coming from a single brain bank, MRC Sudden Death Brain Bank
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TREM2 is a “hub” gene within its module in multiple brain regions including hippocampus
(Forabosco et al. NBA June 2013)
Hippocampus