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Study · Animal study (in vivo) · mouse · 2025

3 results

ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.

Shapira G, Karmon G, Hacohen-Kleiman G, Ganaiem M, Shazman S, Theotokis P, Grigoriadis N, Shomron N, Gozes I

Molecular psychiatry23 Dec 2024Cited by 17 (Europe PMC)

PMID39715923 (opens in a new tab)PMCIDPMC12092271 (opens in a new tab)DOI10.1038/s41380-024-02879-w (opens in a new tab)PepBankPUB-39715923
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Summary

Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer's disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer's disease. While autism is more prevalent in boys and Alzheimer's disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp+/-) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

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

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In male mice with ADNP deficiency, NAP compensated for reduced BrdU labeling.

    In plain wordsIn male mice with ADNP deficiency, NAP compensated for reduced labeling of newly generated cells.

    Peptide
    Davunetide
    Outcome
    IncreaseMale BrdU labeling
    Study

    mousen: not reported in source

    ADNP deficiency or p.Tyr718* mutation
    Outcome group
    Neuroprotection · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Treatment with NAP compensated for the male reduction of BrdU labeling.
    1 context sentence
    Summary · context
    Adnp haplo-insufficient (Adnp+/-) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males.
  2. 02AnimalAnimal study (in vivo)Mechanism

    In mice with the ADNP p.Tyr718* mutation, NAP moderated much of the differential gene expression.

    In plain wordsIn mice with an ADNP mutation, NAP moderated many gene expression differences.

    Peptide
    Davunetide
    Outcome
    Direction not reportedMutation-related differential gene expression
    Study

    mousen: not reported in source

    ADNP deficiency or p.Tyr718* mutation
    Outcome group
    Receptor activity and mechanism · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes.
  3. 03AnimalAnimal study (in vivo)Mechanism

    In mice with the ADNP p.Tyr718* mutation, NAP-associated expression changes included reduced neurotoxic, pro-inflammatory and pro-apoptotic genes.

    In plain wordsIn mice with an ADNP mutation, NAP-associated changes included lower expression of genes linked to toxicity, inflammation and cell death.

    Peptide
    Davunetide
    Outcome
    DecreaseNeurotoxic, pro-inflammatory and pro-apoptotic gene expression
    Study

    mousen: not reported in source

    ADNP deficiency or p.Tyr718* mutation
    Outcome group
    Receptor activity and mechanism · Nervous system and cognition
    Studied dose
    Dose not stated

    Source sentences

    Summary
    NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes.

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.

  1. Version 2Current

    27 Oct 2026, 18:20 UTC

    Study results updated

  2. Version 1

    27 Oct 2026, 16:32 UTC

    First added · source update from Europe PMC

Subjects

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