The characteristic findings in Alzheimer's disease (AD) post-mortem brain (PMB) are degeneration of neurons together with extensive amounts of amyloid deposits (A?42) (a cleavage product of the amyloid precursor protein encoded by the APP gene) and tau (encoded by the MAPT gene). Cerebrospinal fluid (CSF) A?42 and tau levels can predict AD but have a limited reliability in discriminating AD from other neurodegenerative diseases. The apolipoprotein (APOE) ?4 allele and age are currently the only factors strongly associated with late onset AD. The large gaps in our understanding of the genetic aspects of AD may include additional genetic factors that impact age of onset and phenotypic expression of late onset AD. Individual genetic findings (non- synonomous SNPs) associated with complex diseases, such as AD, are unlikely to fully explain the substantial impact of genetic variation on disease pathogenesis. Multilevel etiologic factors are likely to underlie complex diseases and may include multiple loci within and surrounding a gene that influence regulation of transcription and post-transcription, emphasizing the need for integrative evaluation of large genetic regions and correlations with protein biomarker levels as a means for predicting disease risk. This proposal focuses on the overall hypothesis that multiple genetic loci surrounding and within large gene regions act to regulate gene expression in an AD specific manner. During the mentored phase (K99) of this investigation the first aim is to find multiple loci or combinations of SNPs (haplotypes) surrounding and within the APOE, APP and MAPT genes that correlate with expression levels in CSF and PMB. Candidate genetic and protein biomarkers will expand beyond APOE, APP and MAPT genes to include other genes likely to be biologically relevant to neurodegenerative disease.
The second aim i s to demonstrate that putative regulatory haplotypes functionally impact expression by utilizing genomic DNA, containing a particular putative regulatory haplotype, as the active site of gene regulation in reporter and minigene assays. During the independent phase (R00), the final aim is to test regulatory haplotypes for their reliability in discerning between different AD phenotypes and between AD and other neurodegenerative diseases. Collectively, these proposed experiments are unique because they go beyond the simple correlation between core promoter loci and biomarker expression levels by using a combination of genetic, statistical and functional techniques to evaluate the influence of multiple loci within putative distant regulatory elements on AD relevant gene expression to find haplotypes that predict AD. The research and career development components of this K99/R00 application will provide the necessary training for the applicant to become a successful independent investigator who can integrate these techniques to improve our understanding of neurodegenerative disease risk.
Characterization of haplotype regulation of AD relevant expression levels (genetic predictors of biomarkers) may help find new targets for early intervention as well as translate into more accurate ways to predict and thus diagnose AD early in its progression.
|Bekris, Lynn M; Tsuang, Debby W; Peskind, Elaine R et al. (2015) Cerebrospinal fluid AÎ²42 levels and APP processing pathway genes in Parkinson's disease. Mov Disord 30:936-44|
|Bekris, Lynn M; Leverenz, James B (2015) The biomarker and therapeutic potential of miRNA in Alzheimer's disease. Neurodegener Dis Manag 5:61-74|
|Millard, Steven P; Lutz, Franziska; Li, Ge et al. (2014) Association of cerebrospinal fluid A*42 with A2M gene in cognitively normal subjects. Neurobiol Aging 35:357-64|
|Bekris, Lynn M; Lutz, Franziska; Montine, Thomas J et al. (2013) MicroRNA in Alzheimer's disease: an exploratory study in brain, cerebrospinal fluid and plasma. Biomarkers 18:455-66|
|Li, Ge; Bekris, Lynn M; Leong, Lesley et al. (2013) TOMM40 intron 6 poly-T length, age at onset, and neuropathology of AD in individuals with APOE Îµ3/Îµ3. Alzheimers Dement 9:554-61|
|Yu, Chang-En; Cudaback, Eiron; Foraker, Jessica et al. (2013) Epigenetic signature and enhancer activity of the human APOE gene. Hum Mol Genet 22:5036-47|
|Bekris, Lynn M; Lutz, Franziska; Yu, Chang-En (2012) Functional analysis of APOE locus genetic variation implicates regional enhancers in the regulation of both TOMM40 and APOE. J Hum Genet 57:18-25|
|Bekris, Lynn M; Lutz, Franziska; Li, Gail et al. (2012) ADAM10 expression and promoter haplotype in Alzheimer's disease. Neurobiol Aging 33:2229.e1-2229.e9|
|Bekris, Lynn M; Millard, Steve; Lutz, Franziska et al. (2012) Tau phosphorylation pathway genes and cerebrospinal fluid tau levels in Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 159B:874-83|
|Bekris, L M; Galloway, N M; Millard, S et al. (2011) Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease. Neurobiol Aging 32:556.e13-23|
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