Microglial Networks in Alzheimer’s disease

John Hardy j.hardy@ucl.ac.uk

UCL Institute of Neurology United Kingdom

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

Normal Functioning CR1 and TREM2 Promote Neuroprotection by Microglia

Loss of Function of CR1 and TREM2 Promotes Inflammation and Neurotoxicity

TNFa, tumor necrosis factor alpha.

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

TREM2 is a “hub” gene within its module in multiple brain regions including hippocampus

(Forabosco et al. NBA June 2013)

Hippocampus