Alzforum webinar discussion

Jeremy Miller

23 May 2013

Advances of “Integrated Systems…” over many

network studies of dementia

• Large sample size (N>500) produces high-confidence co-expression measurements.

• Extensive characterization of brain pathologyallows modules to be better associated withAlzheimer’s disease.– Pre-mortem assessments of cognitive and

neuropsychiatric impairment (i.e., MMSE, NPI)are also ideal.

• Concurrent SNP genotyping of samplesleads to causal (directed) rather thancorrelational (undirected) networks.

Experimental design

1) Obtain post mortem human hippocampi

from 16 control and 16 AD patients

2) Extract RNA from CA1/CA3 of frozen

hippocampal sections using microscope-

aided dissection

3) Run Illumina microarrays from the RNA

4) Analyze the data using differential

expression and co-expression analysis

*Experiment was performed in

the lab of Dr. Dan Geschwind

AD is a disease of many brain cell types

0.5

0.75

1

1-TOWe performed a network analysis (WGCNA)

on these samples and found several modules

associated with cell type.

A neuronal module shows decreased expression

with AD in CA1 and CA3.

An astrocyte module shows increased

expression with AD in CA1 and CA3.

An oligodendrocyte module is unchanged with

disease, but show increased expression with age

in control.

A microglia module shows increased expression

with increased NFT burden in controls.

Microglia / inflammation markers as an early sign of AD

This microglial module

was a subset of ~400 genes

that showed significantly

increased expression with

NFT burden in controls.

TYROBP is the top hub

gene in this module based

on co-expression!

Many of these hubs

(including TYROBP) are

upregulated in

neurofibrillary tangle-

bearing neurons relative to

non-tangle-bearing neurons

in entorhinal cortex

(Dunckley et al 2006).

These results are consistent with TYROBP as an important

microglial gene, and with microglia playing an important

role in early AD pathogenesis, potentially associated with

NFTs in addition to amyloid pathologies.

Acknowledgements

UCSF:

Mike Oldham

UCLA:

Dan Geschwind Steve Horvath Jeff Goodenbour

Peter Langfelder

Geschwind Lab

Oregon Health Sciences University:

Randy Woltjer

Patti Kramer Jeff Kaye

NRSA (Award #F31 AG031649) Neurobehavioral genetics training program

Oregon Alzheimer’s Disease Center Human Brain and Spinal Fluid Resource Center

Funding:

Tissue:

Data discussed will soon be available in: Jeremy A Miller, Randall L Woltjer, Jeff M Goodenbour,Steve Horvath, and Daniel H Geschwind, "Genes and pathways underlying regional and cell type changes in Alzheimer's disease." Genome Medicine 2013: In Press.