Regional Molecular Mapping of Primate Synapses during Normal Healthy Aging.

Normal mammalian brain aging is characterized by the selective loss of discrete populations of dendritic spines and synapses, particularly affecting neuroanatomical regions such as the hippocampus. Although previous investigations have quantified this morphologically, the molecular pathways orchestrating preferential synaptic vulnerability remain to be elucidated. Using quantitative proteomics and healthy rhesus macaque and human patient brain regional tissues, we have comprehensively profiled the temporal expression of the synaptic proteome throughout the adult lifespan in differentially vulnerable brain regions. Comparative profiling of hippocampal (age vulnerable) and occipital cortex (age resistant) synapses revealed discrete and dynamic alterations in the synaptic proteome, which appear unequivocally conserved between species. The generation of these unique and important datasets will aid in delineating the molecular mechanisms underpinning primate brain aging, in addition to deciphering the regulatory biochemical cascades governing neurodegenerative disease pathogenesis. • Discrete synaptic populations age in a region-dependent manner • Regional heterogeneity in the synaptic proteome is conserved between humans and NHPs • TGF-β1 signaling correlates with regional synaptic vulnerability in aged primate species Graham et al. reveal the regional heterogeneity of synaptic aging and how proteostatic alterations may dictate selective synaptic vulnerability. The authors use comparative proteomic profiling to identify microglial TGF-β1 signaling as a conserved upstream modulator of regional synaptic cascades during aging in both humans and non-human primates (NHPs). [ABSTRACT FROM AUTHOR]