Synaptometry by time-of-flight (SynTOF) mass spectrometry data from NHP

Western and Mediterranean diets differentially affect cerebral cortical
gene expression, brain structure, and socioemotional behavior in
middle-aged, female nonhuman primates (Macaca fascicularis). Here we
quantified the impact of these diets on the presynaptic proteome of
approximately 3.6 million synapses isolated from the lateral temporal
cortex with synaptometry time of flight (SynTOF) mass spectrometry, a
powerful technology for quantifying the molecular diversity of single
presynapses. Associations between the presynaptic proteome, adjacent
cortex transcriptome, and multi-system phenotypes were assessed using a
machine learning approach. Subjects were socially housed macaques (Macaca
fascicularis) randomized to eat Mediterranean (n=17) or Western (n=19)
diets for 31 months prior to brain retrieval. Six presynaptic
proteins (DAT, Aβ42, calreticulin, LC3B, K48-Ubiquitin, SLC6A8) were
elevated in the presynaptic proteome by the Mediterranean compared to the
Western diet (p<0.05). Transcriptomic data from adjacent cortex
predicted all the SynTOF markers. The SPATA22 transcript was positively
correlated with three SynTOF markers (LRRK2, TMEM230 and Aβ40) (all
p<0.05), while TFAP2C was positively correlated with SynTOF markers
pTau, CD47, PARKIN and GAD65 (p<0.05). The multi-system
phenotypes significantly predicted 26 SynTOF markers. The strongest
relationships were between synaptosome GFAP and MRI-determined changes in
white matter (p<0.001). Numerous SynTOF markers were inversely
correlated with hepatosteatosis (e.g., Aβ42, Aβ40, DAT and K48-Ubiquitin
adjusted p’s<0.05), suggesting relationships between liver health
and the presynapse proteome. SynTOF markers were also associated with
behavioral and physiological measures of social environmental stress.
Together these observations demonstrate that diet composition drives
temporal presynaptic protein composition, that transcriptional profiles
strongly predict the presynaptic proteomic profile, and that presynaptic
proteins were closely associated with peripheral metabolism, stress
responsivity, neuroanatomy, and socioemotional behavior. These data
demonstrate brain phenotypes and brain-body interactions which can be
influenced by diet composition, with potential implications for
nutritional approaches to brain and body health.