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P1‐057: Age‐related modulation of the gene expression profile in the hippocampus of triple transgenic Alzheimer and control mice
Author(s) -
Gatta Valentina,
Caporale Teresa,
Stuppia Liborio,
Sensi Stefano L.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.605
Subject(s) - biology , microarray analysis techniques , gene , gene expression , dna microarray , transgene , microarray , genetically modified mouse , gene expression profiling , genetics , microbiology and biotechnology
can be further cleaved by g-secretase to produce a pathogenic Ab42 peptide. Cleavage by a-secretase, produces an APPa fragment and negates pathogenic Ab42 peptide formation. Cerebrospinal fluid (CSF) Ab42 levels are significantly lower in Alzheimer’s disease (AD) patients compared to cognitively normal subjects. The aim of this exploratory investigation was to determine if genetic variation within APP processing pathway genes correlate with CSF levels of APPa, APPb or Ab42, in cognitively normal subjects or AD patients. Methods: CSF was collected from 173 cognitively normal control subjects 52-88 years old and 96 AD patients 52-87 years old. All subjects were genotyped for a total of 19 tagging SNPs within regulatory regions of nine genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, APH1B, NCSTN and PEN2) involved in the APP processing pathway. SNP genotypes were tested for their correlation with CSF APPa, APPb, Ab42 levels (within cases or controls and within SNP genotype groups while using disease status as a covariate), age-at-onset, or AD risk using regression analysis while taking into account age, gender, ethnicity and APOE e4. Results: The two main findings are: 1) ADAM10, an a-secretase gene, SNP rs514049 CC genotype is strongly associated with higher CSF APPa levels in controls (p-value, 0.002) whereas, in contrast, the CC genotype is associated with lower APPa levels in AD (p-value,0.017). The rs514049 CC genotype is also associated with lower Ab42 levels in controls (p-value, 0.044). In addition, a second ADAM10 SNP, the rs2305421 AA genotype is associated with lower APPb levels in AD (p-value, 0.031). 2) Three SNPs (APP rs214484, BACE2 rs12149, and ADAM10 rs2305421) are associated with CSF APPb levels (p-value, 0.009), when all possible interaction terms were entered into a linear regression model while taking into account disease status, age, gender, ethnicity and APOE e4. Conclusions: These results suggest that SNPs within APP processing genes (ADAM10, APP and BACE2) are associated with CSF APP cleavage product levels suggesting that further investigation into the functional contribution and predictive ability of these SNPs may be warranted.