NAD⁺-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer's disease via ATF4-dependent mitochondrial UPR.

Xiong X, Hou J, Zheng Y, Jiang T, Zhao X, Cai J, Huang J, He H, Xu J, Qian S, Lu Y, Wang X and 7 more

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Wang W, Ye Q, Zhou S, Lian M, Xiao J, Song W, Xie C

Cell death & disease11 Oct 2024Cited by 36 (Europe PMC)

PMID39394148PMCIDPMC11470026DOI10.1038/s41419-024-07062-1PepBankPUB-39394148

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Summary

Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer's disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD, explorations to develop a MSR-targeted therapeutic strategy against AD are scarce. We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which NAD⁺-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models. Here, we report dyshomeostasis plasma UPR^mt-mitophagy-mediated MSR profiles in AD patient samples. NMN restores NAD⁺ metabolic profiles and improves MSR through the ATF4-dependent UPR^mt pathway in AD-related cross-species models. At the organismal level, NAD⁺ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD. Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes. In brief, our work provides evidence that MSR has an active role in the pathogenesis of AD, as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely, bolstering mitochondrial proteostasis by NMN decreases protein aggregation, restores memory performance, and delays disease progression, ultimately translating to increased healthspan.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study7

7 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Mechanism
In AD mice, NMN ameliorated mitochondrial proteotoxicity.
In plain wordsIn mice with AD, NMN reduced mitochondrial protein toxicity.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseMitochondrial proteotoxicity
Study
mousen: not reported in source
Alzheimer disease model
Outcome group
Mitochondrial function · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
At the organismal level, NAD⁺ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD.
Show in the study text Report a problemFND-3939414803
02AnimalAnimal study (in vivo)Mechanism
In AD mice, NMN decreased hippocampal synaptic disruption.
In plain wordsIn mice with AD, NMN reduced disruption of hippocampal nerve connections.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseHippocampal synaptic disruption
Study
mousen: not reported in source
Alzheimer disease model
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
At the organismal level, NAD⁺ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD.
Show in the study text Report a problemFND-3939414804
03AnimalAnimal study (in vivo)Mechanism
In AD mice, NMN decreased neuronal loss.
In plain wordsIn mice with AD, NMN reduced nerve cell loss.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseNeuronal loss
Study
mousen: not reported in source
Alzheimer disease model
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
At the organismal level, NAD⁺ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD.
Show in the study text Report a problemFND-3939414805
04AnimalAnimal study (in vivo)Mechanism
In AD mice, NMN decreased brain atrophy.
In plain wordsIn mice with AD, NMN reduced brain shrinkage.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
DecreaseBrain atrophy
Study
mousen: not reported in source
Alzheimer disease model
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
At the organismal level, NAD⁺ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD.
Show in the study text Report a problemFND-3939414806
05AnimalAnimal study (in vivo)Mechanism
In the hippocampus, NMN altered MSR-associated genes and proteins principally in astrocytes rather than microglia and oligodendrocytes.
In plain wordsIn mice, NMN changed stress-response genes and proteins mainly in astrocytes rather than microglia and oligodendrocytes.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
MixedAstrocyte MSR transcriptional changes
Study
mousen: not reported in source
Alzheimer disease model
Outcome group
Mitochondrial function · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes.
Show in the study text Report a problemFND-3939414807
06AnimalOther designMechanism
In AD-related cross-species models, NMN restored NAD metabolic profiles.
In plain wordsIn AD models, NMN restored NAD metabolic profiles.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
Direction not reportedNAD metabolic profiles
Study
n: not reported in source
AD-related cross-species models
Outcome group
Mitochondrial function · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
NMN restores NAD⁺ metabolic profiles and improves MSR through the ATF4-dependent UPR^mt pathway in AD-related cross-species models.
Show in the study text Report a problemFND-3939414801
07AnimalOther designMechanism
In AD-related cross-species models, NMN improved mitochondrial stress responses through ATF4-dependent mitochondrial UPR.
In plain wordsIn AD models, NMN improved mitochondrial stress responses through an ATF4-dependent pathway.
Peptide
NMN (nicotinamide mononucleotide)
Outcome
IncreaseMitochondrial stress response
Study
n: not reported in source
AD-related cross-species models
Outcome group
Mitochondrial function · Nervous system and cognition
Studied dose
Dose not stated
Source sentences
Summary
NMN restores NAD⁺ metabolic profiles and improves MSR through the ATF4-dependent UPR^mt pathway in AD-related cross-species models.
Show in the study text Report a problemFND-3939414802

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
21 Oct 2026, 15:58 UTC
Study results updated
Version 1
21 Oct 2026, 12:50 UTC
First added · source update from Europe PMC

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