posted on 2023-03-13, 12:42authored byJames
P. Quinn, Elizabeth C. Ethier, Angelo Novielli, Aygul Malone, Christopher E. Ramirez, Lauren Salloum, Bianca A. Trombetta, Pia Kivisäkk, Michael Bremang, Stefan Selzer, Marjorie Fournier, Sudeshna Das, Yaoyi Xing, Steven E. Arnold, Becky C. Carlyle
The
granin neuropeptide family is composed of acidic secretory
signaling molecules that act throughout the nervous system to help
modulate synaptic signaling and neural activity. Granin neuropeptides
have been shown to be dysregulated in different forms of dementia,
including Alzheimer’s disease (AD). Recent studies have suggested
that the granin neuropeptides and their protease-cleaved bioactive
peptides (proteoforms) may act as both powerful drivers of gene expression
and as a biomarker of synaptic health in AD. The complexity of granin
proteoforms in human cerebrospinal fluid (CSF) and brain tissue has
not been directly addressed. We developed a reliable nontryptic mass
spectrometry assay to comprehensively map and quantify endogenous
neuropeptide proteoforms in the brain and CSF of individuals diagnosed
with mild cognitive impairment and dementia due to AD compared to
healthy controls, individuals with preserved cognition despite AD
pathology (“Resilient”), and those with impaired cognition
but no AD or other discernible pathology (“Frail”).
We drew associations between neuropeptide proteoforms, cognitive status,
and AD pathology values. Decreased levels of VGF proteoforms were
observed in CSF and brain tissue from individuals with AD compared
to controls, while select proteoforms from chromogranin A showed the
opposite effect. To address mechanisms of neuropeptide proteoform
regulation, we showed that the proteases Calpain-1 and Cathepsin S
can cleave chromogranin A, secretogranin-1, and VGF into proteoforms
found in both the brain and CSF. We were unable to demonstrate differences
in protease abundance in protein extracts from matched brains, suggesting
that regulation may occur at the level of transcription.