Abstract Details

Title Decreased Expression of Peptidase Inhibitors in Peripheral Blood from Familial Alzheimer's Disease Mutation Carriers

Topic Aging and Dementia

Presentation(s) S34 - (-)

Poster/Presentation
Number 004

Objective

Background Gene expression studies in peripheral tissues from patients with neurodegenerative disorders can provide insights into disease pathogenesis, and identify potential biomarkers. Persons inheriting PSEN1 mutations causing FAD provide an opportunity to study changes during the preclinical period. With microarrays, we studied mRNA from total blood from carriers of PSEN1 mutations (MCs) and non-carriers (NCs), to identify a peripheral gene expression phenotype.

Design/Methods Clinical assessments were performed and peripheral blood was obtained from 22 non-demented persons from 15 families with 10 distinct PSEN1 mutations. Total RNA was extracted from peripheral blood and hybridized on to Illumina gene expression microarrays. Data analysis included comparisons between MCs and NCs.

Results 15 individuals were MCs and 7 individuals were NCs. Six MCs had CDR scores of 0.5 and the rest were asymptomatic. Mean age of MCs was 38 years, an estimated 11 years before the age of dementia diagnosis in their affected parent. There were no differences between MCs and NCs with regard to age, gender, or MMSE score. We identified 271 differentially expressed probes (152 upregulated, 119 downregulated) between MCs and NCs at p<0.005. Gene ontology analysis revealed a number of affected cell functions, including DNA binding, endocytosis, and RNA splicing. We detected reduced (by [sim]35%) levels of the serpin peptidase inhibitor (SERPINE2) and another peptidase inhibitor (skin-derived, PI3) mRNA.

Conclusions SERPINE2, which was reduced in PSEN1 MCs has been linked to neurite outgrowth activity, and its expression reduced in AD brains. Though the mechanism by which protease inhibitor mRNA are diminished in FAD MC plasma is unclear, such a decline could contribute to neuronal injury. Peripheral disease biomarkers should prove valuable for assessing drug efficacy and provide new pathophysiological insights.

Authors/Disclosures
John M. Ringman, MD, FAAN (Keck School of Medicine of USC, Neurology Dept) PRESENTER	The institution of Dr. Ringman has received research support from Avid Pharmaceuticals. The institution of Dr. Ringman has received research support from AltaMed. The institution of Dr. Ringman has received research support from CurePSP.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Eric Klein	No disclosure on file
	No disclosure on file
Kristy Hwang	No disclosure on file
Liana Apostolova, MD, FAAN (Indiana University School of Medicine)	Dr. Apostolova has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NIH. Dr. Apostolova has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Apostolova has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Apostolova has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Apostolova has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Apostolova has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Apostolova has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Apostolova has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Alzheimer Association. An immediate family member of Dr. Apostolova has stock in Cassava Neurosciences. The institution of Dr. Apostolova has received research support from Roche Diagnostics. The institution of Dr. Apostolova has received research support from NIA. The institution of Dr. Apostolova has received research support from Alzheimer Association. The institution of Dr. Apostolova has received research support from AVID radiopharmaceuticals. The institution of Dr. Apostolova has received research support from Life Molecular Imaging.
Giovanni Coppola, MD (UCLA)	Dr. Coppola has received personal compensation for serving as an employee of Regeneron. Dr. Coppola has received stock or an ownership interest from Regeneron.

��ɫ��

��ɫ��