Abstract
INTRODUCTION: Widespread disruption of neuropeptide (NP) networks in Alzheimer's disease (AD) and disproportionate absence of neurons expressing high NP-producing, coined as HNP neurons, have been reported for the entorhinal cortex (EC) of AD brains. Hypothesizing that functional features of HNP neurons are involved in the early pathogenesis of AD, we aim to understand the molecular mechanisms underlying these observations. METHODS: Multiscale and spatiotemporal transcriptomic analysis was used to investigate AD-afflicted and healthy brains. Our focus encompassed NP expression dynamics in AD, AD-associated NPs (ADNPs) trajectories with aging, and the neuroanatomical distribution of HNP neuron. RESULTS: Findings include that 1) HNP neurons exhibited heightened metabolic needs and an upregulation of gene expressions linked to protein misfolding; 2) dysfunctions of ADNP production occurred in aging and mild cognitive decline; 3) HNP neurons co-expressing ADNPs were preferentially distributed in brain regions susceptible to AD. DISCUSSION: We identified potential mechanisms that contribute to the selective vulnerability of HNP neurons to AD. Our results indicate that the functions of HNP neurons predispose them to oxidative stress and protein misfolding, potentially serving as inception sites for misfolded proteins in AD.