Alzforum webinar discussionJeremy Miller23 May 2013
Advances of “Integrated Systems…” over manynetwork 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 andneuropsychiatric impairment (i.e., MMSE, NPI)are also ideal.• Concurrent SNP genotyping of samplesleads to causal (directed) rather thancorrelational (undirected) networks.
Experimental design1) Obtain post mortem human hippocampifrom 16 control and 16 AD patients2) Extract RNA from CA1/CA3 of frozenhippocampal sections using microscope-aided dissection3) Run Illumina microarrays from the RNA4) Analyze the data using differentialexpression and co-expression analysis*Experiment was performed inthe lab of Dr. Dan Geschwind
AD is a disease of many brain cell types0.50.7511-TOWe performed a network analysis (WGCNA)on these samples and found several modulesassociated with cell type.A neuronal module shows decreased expressionwith AD in CA1 and CA3.An astrocyte module shows increasedexpression with AD in CA1 and CA3.An oligodendrocyte module is unchanged withdisease, but show increased expression with agein control.A microglia module shows increased expressionwith increased NFT burden in controls.
Microglia / inflammation markers as an early sign of ADThis microglial modulewas a subset of ~400 genesthat showed significantlyincreased expression withNFT burden in controls.TYROBP is the top hubgene in this module basedon co-expression!Many of these hubs(including TYROBP) areupregulated inneurofibrillary tangle-bearing neurons relative tonon-tangle-bearing neuronsin entorhinal cortex(Dunckley et al 2006).These results are consistent with TYROBP as an importantmicroglial gene, and with microglia playing an importantrole in early AD pathogenesis, potentially associated withNFTs in addition to amyloid pathologies.
AcknowledgementsUCSF:Mike OldhamUCLA:Dan GeschwindSteve HorvathJeff GoodenbourPeter LangfelderGeschwind LabOregon Health Sciences University:Randy WoltjerPatti KramerJeff KayeNRSA (Award #F31 AG031649)Neurobehavioral genetics training programOregon Alzheimer’s Disease CenterHuman Brain and Spinal Fluid Resource CenterFunding:Tissue:Data discussed will soon be available in:Jeremy A Miller, Randall L Woltjer, Jeff M Goodenbour,Steve Horvath, andDaniel H Geschwind, "Genes and pathways underlying regional and celltype changes in Alzheimers disease." Genome Medicine 2013: In Press.