Unacylated-Ghrelin Impairs Hippocampal Neurogenesis and Memory in Mice and Is Altered in Parkinson’s Dementia in Humans
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Abstract
Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT −/− ) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT + cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia.
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PD patients have reduced plasma ghrelin levels in the fasting state and impaired ghrelin response and secretion in the postprandial state.
“Evidence from PD patients has identified reduced plasma ghrelin levels in the fasting state”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [564]
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ResultAcylated but not des‐acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson's disease
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Berrout, L., & Isokawa, M. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.04.009 · Cited by 31 · cited 1× · see citing works
“In addition, as acyl-ghrelin promotes F-actin expression in hippocampal dendrites it is linked with the generation and re-modeling of spines.(42) Therefore, we analyzed dendritic spines on hippocampal neurons from WT and GOAT / mice.”
Less is more: Caloric regulation of neurogenesis and adult brain function
Morgan, A. H., Andrews, Z. B., & Davies, J. S. (2017) · Journal of Neuroendocrinology · doi:10.1111/jne.12512 · Cited by 20 · cited 1× · see citing works
“We therefore propose that acyl-ghrelin promotes hippocampal neurogenesis in a non-cell-autonomous manner.(22,50) To validate this, we show that acyl-ghrelin treatment of hippocampal NSPCs in vitro had no effect on cell proliferation—a result that was consistent with the absence of detectable GHS-R expression in these…”
ResultSelf-citationWesnes, K. A. (2014) · Journal of Alzheimer’s Disease & Parkinsonism · doi:10.4172/2161-0460.1000131 · Cited by 8 · cited 6× · see citing works
“This change may reflect a homeostatic response to the reduction in plasma AG:UAG and therefore attenuated hippocampal ghrelin-signaling in PDD.”
BackgroundInfluential
Flagged first, then by citations
Cited by
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
Pharmacological Management of Apathy in Dementia
Azhar, L., Kusumo, R. W., Marotta, G., Lanctôt, K., & Herrmann, N. (2022) · CNS Drugs · doi:10.1007/s40263-021-00883-0 · Cited by 39 · see citing works
“In patients with PD dementia, studies observed altered gut microbiota and consequently altered PYY levels and a significant increase in unacylated ghrelin, associated with reduced neurogenesis and neuronal plasticity [133, 134].”
BackgroundPark, M., Park, K. H., Choi, B. J., Han, W.-H., Yoon, H. J., Jung, H. Y., Lee, J. W., Song, I., Lim, D., Choi, M., et al. (2022) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2115082119 · Cited by 23 · see citing works
“The cells detected by c-Fos, which is associated with changes in neuronal gene expression that promote learning and memory function (23, 48), also were increased by KARI 201 treatment in APP/PS1 mice (Fig.”
BackgroundGhrelin-Mediated Regeneration and Plasticity After Nervous System Injury
Stoyanova, I., & Lutz, D. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.595914 · Cited by 23 · see citing works
Metabolic hormones mediate cognition
Ghosh‐Swaby, O. R., Reichelt, A. C., Sheppard, P. A. S., Davies, J. S., Bussey, T. J., & Saksida, L. M. (2022) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2022.101009 · Cited by 25 · see citing works
Self-citationGhrelin mediated hippocampal neurogenesis.
Davies, J. (2022) · Vitamins and hormones · doi:10.1016/bs.vh.2021.12.003 · Cited by 12 · see citing works
Self-citationTargeting G Protein-Coupled Receptors in the Treatment of Parkinson's Disease.
Jones-Tabah, J. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167927 · Cited by 18 · see citing works
Acylation, a Conductor of Ghrelin Function in Brain Health and Disease
Thomas, A. S., Sassi, M., Angelini, R., Morgan, A. H., & Davies, J. S. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.831641 · Cited by 17 · see citing works
Self-citationThe 5:2 diet does not increase adult hippocampal neurogenesis or enhance spatial memory in mice
Roberts, L. D., Hornsby, A., Thomas, A., Sassi, M., Kinzett, A., Hsiao, N., David, B. R., Good, M., Wells, T., & Davies, J. (2022) · bioRxiv · doi:10.15252/embr.202357269 · Cited by 11 · see citing works
“More recently, we showed that acyl-ghrelin increased BDNF mRNA — a neurotrophic factor — within the granule cell layer of the hippocampus (Hornsby et al , 2020).”
BackgroundSelf-citationGhrelin Acylation—A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis
Sassi, M., Morgan, A., & Davies, J. (2022) · Cells · doi:10.3390/cells11050765 · Cited by 10 · see citing works
Self-citationYu, M., Zhu, Q., Niu, M., Li, N., Ren, B.-Q., Yu, T., Zhou, Z., Guo, J., & Zhou, Y. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-00859-w · Cited by 11 · see citing works
The Pathologic Roles and Therapeutic Implications of Ghrelin/GHSR System in Mental Disorders
Mao, Q., Wang, J., Yang, Z., Ding, R., Lv, S.-Y., & Ji, X.-Y. (2024) · Depression and Anxiety · doi:10.1155/2024/5537319 · Cited by 10 · see citing works
“In addition, in terms of neurogenesis, des-acyl ghrelin and acyl-ghrelin may play opposite roles, and changes in their ratios may be associated with certain neurodegenerative diseases [12, 13].”
Advances in neural stem cells in aging and age-related neurodegenerative diseases
Zhong, R.-J., Huang, W.-H., Chen, C., Zhang, B.-R., Pu, J.-L., & Zhang, F. (2025) · Ageing and Neurodegenerative Diseases · doi:10.20517/and.2024.32 · Cited by 10 · see citing works
Han, S., Utami, R., Qin, Y., Liam-or, R., Sreedharan, J., Davies, J. S., & Al-Jamal, K. T. (2025) · Small · doi:10.1002/smll.202504517 · Cited by 8 · see citing works
Self-citationLi, N., Li, N., Xu, F., Yu, M., Qiao, Z., & Zhou, Y. (2021) · Molecular Brain · doi:10.1186/s13041-021-00866-8 · Cited by 8 · see citing works
Li, N., Li, N., Yang, L., Gu, H.-T., Ji, J., Zhou, H.-L., Zhu, Q., Yu, M., Sun, Y.-X., & Zhou, Y. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac230 · Cited by 8 · see citing works
Acyl-Ghrelin Attenuates Neurochemical and Motor Deficits in the 6-OHDA Model of Parkinson’s Disease
Rees, D. J., Beynon, A. L., Lelos, M. J., Smith, G. A., Roberts, L. D., Phelps, L., Dunnett, S. B., Morgan, A. H., Brown, M. R., Wells, T., et al. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01282-9 · Cited by 9 · see citing works
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Sharma, V., Sharma, P., Mannan, A., Dhiman, S., Mohan, M., Singh, S., & Singh, T. G. (2025) · Behavioural Brain Research · doi:10.1016/j.bbr.2025.115720 · Cited by 6 · see citing works
Ghrelin’s role in sleep and sleep deprivation: a narrative review
Ditmer, M., Wojtera, A., Gabryelska, A., Turkiewicz, S., Białasiewicz, P., Strzelecki, D., & Sochal, M. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1744781 · Cited by 6 · see citing works
Therapeutic potential of ghrelin/GOAT/GHSR system in gastrointestinal disorders
Ma, Y., Yan, Q., Wang, P., Guo, W., & Yu, L. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1422431 · Cited by 6 · see citing works
Gouveia, H. J. C. B., dos Santos, O. H., & Frasnelli, J. (2025) · npj Parkinson s Disease · doi:10.1038/s41531-025-01066-0 · Cited by 5 · see citing works
“…assessment of bias related to confounding factors, most studies showed a low risk of bias and good internal validity when comparing similar groups in aspects such as age, sex, weight, and body mass index 26,33,35 – 37 , with only one study showing signi fi cant differences between the groups 38 .”
InfluentialRout, S., Dash, R. J., Satish, V., Venugopal, G., Rao, B. N., Bandhyopadhyay, D., Bhoi, S. K., & Ramadass, B. (2025) · Aging · doi:10.18632/aging.206200 · Cited by 5 · see citing works
Astrocytes of the hippocampus and responses to periprandial neuroendocrine hormones
Loera‐Lopez, A. L., Lord, M. N., & Noble, E. E. (2025) · Physiology & Behavior · doi:10.1016/j.physbeh.2025.114913 · Cited by 2 · see citing works
Thrifty Hormone Ghrelin: The Secret of Aging Muscularly.
Sun, Y. (2020) · PubMed · Cited by 2 · see citing works
Stark, R., Zigman, J., & Andrews, Z. (2025) · Journal of neuroendocrinology · doi:10.1111/jne.70096 · Cited by 1 · see citing works
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Carisi, M. C., Howell, O. W., Morgan, A. H., & Davies, J. S. (2022) · STAR Protocols · doi:10.1016/j.xpro.2022.101896 · Cited by 1 · see citing works
Self-citationGhrelin-axis function in the context of Adult Hippocampal Neurogenesis
Hornsby, A. K. E. (2018) · doi:10.23889/suthesis.50587
Self-citationCharacterisation of the ghrelinergic system in human models of neurodegenerative diseases
Carisi, M. C. (2021) · doi:10.23889/suthesis.58915
Self-citationLi, N., Gu, H., Yu, M., Wei, C., Li, N., Zhu, Q., Zhou, H., Yu, T., Sun, Y., & Zhou, Y. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3944544
Nodweddu effaith signalu ghrelin-GHS-R ar awtoffagi niwronaidd
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“Given that GHSR is highly expressed throughout the granule cell layer of the hippocampus, 23,46 the action of ghrelin at GHSR is essential for ghrelin-induced AHN 23,47 and is opposed by UAG, 48 it was surprising that AHN in HAB rats was elevated in both rostral and caudal portions.”
Self-citationLi, N., Li, N., Xu, F., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16800139
- Authors
- Hornsby, A. K. E., Buntwal, L., Carisi, M. C., Santos, V. V., Johnston, F., Roberts, L. D., Sassi, M., Mequinion, M., Stark, R., Reichenbach, A., Lockie, S. H., Siervo, M., Howell, O., Morgan, A. H., Wells, T., Andrews, Z. B., Burn, D. J., & Davies, J. S.
- Affiliations
- Swansea University (GB)
- Monash University (AU)
- Newcastle University (GB)
- University of Nottingham (GB)
- Cardiff University (GB)
- Corresponding author
- Davies, Jeffrey S.
- ORCID
- Venue
- Cell Reports Medicine
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 1
- Issue
- 7
- Pages
- 100120
- ISSN
- 2666-3791 (ISSN-L)
- PMC
- PMC7575905
- OpenAlex
- W3094417216
- Semantic Scholar
- 13dfd5af86b7291e9d7a2217469945af381d97ef
- Cited by
- 35
- References
- 68
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 4 · 2023: 1 · 2022: 12 · 2021: 5 · 2020: 1 · 2018: 1
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports Medicine (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- National Health and Medical Research Council (APP1154974)
- Royal Society
- Medical Research Council (G0902250)
- Eli Lilly and Company
- Swansea University
- Parkinson's UK
- Newcastle University
- British Society for Neuroendocrinology
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- unacylated ghrelin, acylated ghrelin, ghrelin O-acyltransferase, hippocampal neurogenesis, spatial memory, neuroplasticity, BDNF signaling, Parkinson's disease dementia, circulating biomarkers, growth hormone secretagogue receptor
- MeSH terms
- Acyltransferases, Animals, Cognition, Disease Models, Animal, Female, Gene Expression Regulation, Hippocampus, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Neuronal Plasticity, Neurons, Parkinson Disease, Supranuclear Palsy, Progressive, Signal Transduction, Mice, Knockout, Brain-Derived Neurotrophic Factor, Mice, Rats, Ghrelin, Neurogenesis, Primary Cell Culture, Spatial Memory
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