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MOLECULAR COMPOSITION OF ENTORHINAL SYNAPSES IN PRIMARY AGE-RELATED TAUOPATHY AND ALZHEIMER’S DISEASE
Abstract
Aims
To compare the composition of synapses within the entorhinal cortex (EC) between non-pathological controls, Alzheimer’s disease (AD) and primary age-related tauopathy (PART).
Methods
We prepared synaptosomal fractions from the EC of brains without lesions (n=5), with AD (n=8) or PART (n=5) pathology and analyzed the fractions by LC-MS/MS. We normalized peptides using variance stabilizing normalization and to the total intensity of 15 core synaptic proteins. We used MSqRob to compare synaptic protein levels across groups by linear mixed effects regression. Random effects included peptide sequence/modification, run, post-mortem interval and age-at-death. We performed statistical enrichment tests to compare group differences in relative abundance of gene ontologies. All p-values were adjusted for false discovery rate.
Results
We identified 3473 proteins with at least 1 proteotypic peptide. 5 proteins were under-expressed and 44 proteins were over-expressed in AD compared to controls (adj.p<.05). No individual protein was altered between PART and controls (all adj.p>.15). 3 proteins were under-expressed in PART compared to AD (adj.p<.03). Compared to controls, both AD and PART synaptosomes were under-enriched for pathways including vesicle-mediated transport, signal transduction and nervous system development and over-enriched for pathways including mitochondrial transmembrane transport, ATP synthesis and aerobic respiration (adj.p<.05). PART synapses were specifically under-enriched for pathways related to actin filament polymerization and over-enriched for RNA processing. AD synapses were specifically under-enriched for endopeptidase activity and endosomal sorting and over-enriched for mitochondrial gene expression. No ontologies were differentially enriched between PART and AD synaptosomes (adj.p>.05).
Conclusions
AD and PART pathologies affect similar synaptic processes in the EC.