Proteomic signatures of cognitive resilience in LOU/c/Jall rats converge with inverse hippocampal axes of Alzheimer disease.

Abstract

Why some individuals maintain good level of cognitive performances during aging, others dont or even progress toward Alzheimers disease. We profiled the hippocampal proteome of adult LOU/c/Jall rats, a strain associated with spontaneous cognitive longevity, and compared this proteomic state with a published human hippocampal Alzheimers disease dataset. Because individual protein changes did not survive proteome-wide correction, interpretation was based on convergent pathway-level, cell-type enrichment and cross-species directional analyses. The LOU hippocampus displayed a structured remodeling of mitochondrial, lysosomal, proteostatic and synaptic systems. Oligodendrocyte-associated nuclear-encoded complex I/III components were reduced, whereas neuronal mitochondrial aminoacyl-tRNA synthetases, V-ATPase, SNARE-related proteins and inhibitory-transmission markers were increased. CD200 was markedly reduced, but this occurred without accompanying complement, microglial, astrocytic or inflammatory activation signatures. Cross-species overlay indicated that several LOU-associated axes were directionally opposed to late Alzheimers disease, particularly synaptic vesicle and inhibitory-transmission programs, whereas myelin-associated changes occupied a lower-amplitude and non-inflammatory position along an axis altered in early Alzheimers disease. These findings identify a hippocampal proteomic configuration associated with the LOU resilience phenotype and suggest that successful brain aging and Alzheimers disease may involve opposing states of shared hippocampal molecular systems. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/735140v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@8a1a17org.highwire.dtl.DTLVardef@b7023corg.highwire.dtl.DTLVardef@f3ca20org.highwire.dtl.DTLVardef@15b1b29_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHippocampal proteome of the LOU/c/Jall rat at 3 months profiled by DIA-MS C_LIO_LICoordinated reduction of complex I/III subunits in oligodendrocytes C_LIO_LINeuronal aminoacyl-tRNA synthetases, V-ATPase and SNARE machinery up-regulated C_LIO_LIMarked reduction of CD200 with no inflammatory correlate C_LIO_LILate human AD hippocampal transcriptome moves opposite to adult LOU C_LI