Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer's disease.

Introduction: Abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in Alzheimer's disease (AD). We hypothesize that NP network disruption is widespread in AD brains.

Methods: Single-cell transcriptomic data from the entorhinal cortex (EC) were used to investigate the NP network disruption in AD. Bulk RNA-sequencing data generated from the temporal cortex by independent groups and machine learning were employed to identify key NPs involved in AD. The relationship between aging and AD-associated NP (ADNP) expression was studied using GTEx data.

Results: The proportion of cells expressing NPs but not their receptors decreased significantly in AD. Neurons expressing higher level and greater diversity of NPs were disproportionately absent in AD. Increased age coincides with decreased ADNP expression in the hippocampus.

Discussion: NP network disruption is widespread in AD EC. Neurons expressing more NPs may be selectively vulnerable to AD. Decreased expression of NPs participates in early AD pathogenesis. We predict that the NP network can be harnessed for treatment and/or early diagnosis of AD.