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

Li, Manci; Larsen, Peter A.

doi:10.1002/alz.12979

Cited by 4 publications

(24 citation statements)

References 109 publications

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“…We observed a similar absence of HNP neurons in AD (Figure 2B; Table S4). 8 We previously reported a significant reduction of HNP neurons expressing more neuropeptides in the EC of AD brains. As we hypothesized that HNP neurons would experience greater energetic demands and higher metabolic stress, we predicted that HNP neurons would show more metabolic activity.…”

Section: Alterations Of Hnp Neuronal Abundance and Functions In Ad: O...mentioning

confidence: 89%

“…A closer examination of the NPs that demonstrated a decrease in expression with age in the aforementioned brain regions revealed that these NPs consisted of expressed ADNPs included in our previous study. 8 To support the specificity of the observed change in ADNP expression, we analyzed the counts of all non-ADNP NPs in the brain regions under examination and found no age-related changes in their overall levels (Table S10). In short, the spatiotemporal transcriptome analysis presented here showed that the decrease of NPs in the aging human brain was specific to brain regions and NPs implicated in AD, supporting that age-related cognitive decline shares mechanisms with AD and may be mediated by loss of ADNP expression during aging.…”

Section: Loss Of Adnp Expression Participates In Early Pathogenesis O...mentioning

confidence: 98%

“…7 We recently showed the widespread disruption of neuropeptide (NP) networks in AD and the disproportionate absence of cells, mostly neurons, expressing higher levels and diversities of NPs (high NP-producing/HNP cells/neurons) in the entorhinal cortex (EC) of AD brains. 8 As steps involved in NP production are energy-intensive and HNP neurons dedicated more transcription power to NP production, we hypothesized that HNP neurons face greater energetic demands and higher metabolic stress during aging. 8 However, the functional characteristics of HNP neurons and the relationship between NP co-expression and other established pathological features of AD are unclear.…”

Section: Introductionmentioning

confidence: 99%

“…8 As steps involved in NP production are energy-intensive and HNP neurons dedicated more transcription power to NP production, we hypothesized that HNP neurons face greater energetic demands and higher metabolic stress during aging. 8 However, the functional characteristics of HNP neurons and the relationship between NP co-expression and other established pathological features of AD are unclear. Although the expression of AD-associated NPs (ADNPs) decreased in the hippocampus during natural aging, 8 the role of HNP neurons co-expressing ADNPs in influencing cognitive functions and mediating regional brain vulnerability is yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

“…8 However, the functional characteristics of HNP neurons and the relationship between NP co-expression and other established pathological features of AD are unclear. Although the expression of AD-associated NPs (ADNPs) decreased in the hippocampus during natural aging, 8 the role of HNP neurons co-expressing ADNPs in influencing cognitive functions and mediating regional brain vulnerability is yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Multifaceted impact of specialized neuropeptide-intensive neurons on the selective vulnerability in Alzheimer’s disease

Li,

Flack,

Larsen

2023

Preprint

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INTRODUCTIONWidespread disruption of neuropeptide (NP) networks in Alzheimer’s disease (AD) and disproportionate absence of neurons expressinghighNP-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.METHODSMultiscale and spatiotemporal transcriptomic analysis was used to investigate AD-afflicted and healthy brains. Our focus encompassed NP expression dynamics in AD,AD-associatedNPs (ADNPs) trajectories with aging, and the neuroanatomical distribution of HNP neuron.RESULTSFindings 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.DISCUSSIONWe 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.

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Section: Alterations Of Hnp Neuronal Abundance and Functions In Ad: O...mentioning

confidence: 89%

Section: Loss Of Adnp Expression Participates In Early Pathogenesis O...mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Multifaceted impact of specialized neuropeptide-intensive neurons on the selective vulnerability in Alzheimer’s disease

Li,

Flack,

Larsen

2023

Preprint

Self Cite

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Alzheimer’s disease and sleep disorders: A bidirectional relationship

Chen,

Peng,

Sun

2024

Neuroscience

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Cerebrospinal Fluid and Brain Proteoforms of the Granin Neuropeptide Family in Alzheimer’s Disease

Quinn

Ethier

Novielli

et al. 2023

J. Am. Soc. Mass Spectrom.

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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.

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

Cited by 4 publications

References 109 publications

Multifaceted impact of specialized neuropeptide-intensive neurons on the selective vulnerability in Alzheimer’s disease

Multifaceted impact of specialized neuropeptide-intensive neurons on the selective vulnerability in Alzheimer’s disease

Alzheimer’s disease and sleep disorders: A bidirectional relationship

Cerebrospinal Fluid and Brain Proteoforms of the Granin Neuropeptide Family in Alzheimer’s Disease

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