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

Why some individuals maintain good level of cognitive performances during aging, others don’t or even progress toward Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s 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 Alzheimer’s disease. These findings identify a hippocampal proteomic configuration associated with the LOU resilience phenotype and suggest that successful brain aging and Alzheimer’s disease may involve opposing states of shared hippocampal molecular systems.