Dysregulation of Neuropeptide and Tau Peptide Signatures in Human Alzheimer’s Disease Brain

Synaptic
dysfunction
and loss occur in Alzheimer’s disease
(AD) brains, which results in cognitive deficits and brain neurodegeneration.
Neuropeptides comprise the major group of synaptic neurotransmitters
in the nervous system. This study evaluated neuropeptide signatures
that are hypothesized to differ in human AD brain compared to age-matched
controls, achieved by global neuropeptidomics analysis of human brain
cortex synaptosomes. Neuropeptidomics demonstrated distinct profiles
of neuropeptides in AD compared to controls consisting of neuropeptides
derived from chromogranin A (CHGA) and granins, VGF (nerve growth
factor inducible), cholecystokinin, and others. The differential neuropeptide
signatures indicated differences in proteolytic processing of their
proneuropeptides. Analysis of cleavage sites showed that dibasic residues
at the N-termini and C-termini of neuropeptides were the main sites
for proneuropeptide processing, and data also showed that the AD group
displayed differences in preferred residues adjacent to the cleavage
sites. Notably, tau peptide signatures differed in the AD compared
to age-matched control human brain cortex synaptosomes. Unique tau
peptides were derived from the tau protein through proteolysis using
similar and differential cleavage sites in the AD brain cortex compared
to the control. Protease profiles differed in the AD compared to control,
indicated by proteomics data. Overall, these results demonstrate that
dysregulation of neuropeptides and tau peptides occurs in AD brain
cortex synaptosomes compared to age-matched controls, involving differential
cleavage site properties for proteolytic processing of precursor proteins.
These dynamic changes in neuropeptides and tau peptide signatures
may be associated with the severe cognitive deficits of AD.