Adiponectin-Mimetic Novel Nonapeptide Rescues Aberrant Neuronal Metabolic-Associated Memory Deficits in Alzheimer’s Disease
Open accessAbstract
BACKGROUND: Recently, we and other researchers reported that brain metabolic disorders are implicated in Alzheimer's disease (AD), a progressive, devastating and incurable neurodegenerative disease. Hence, novel therapeutic approaches are urgently needed to explore potential and novel therapeutic targets/agents for the treatment of AD. The neuronal adiponectin receptor 1 (AdipoR1) is an emerging potential target for intervention in metabolic-associated AD. We aimed to validate this hypothesis and explore in-depth the therapeutic effects of an osmotin-derived adiponectin-mimetic novel nonapeptide (Os-pep) on metabolic-associated AD. METHODS: We used an Os-pep dosage regimen (5 μg/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid β oligomer-injected, transgenic adiponectin knockout (Adipo-/-) and AdipoR1 knockdown mice. After behavioral studies, brain tissues were subjected to biochemical and immunohistochemical analyses. In separate cohorts of mice, electrophysiolocal and Golgi staining experiments were performed. To validate the in vivo studies, we used human APP Swedish (swe)/Indiana (ind)-overexpressing neuroblastoma SH-SY5Y cells, which were subjected to knockdown of AdipoR1 and APMK with siRNAs, treated with Os-pep and other conditions as per the mechanistic approach, and we proceeded to perform further biochemical analyses. RESULTS: Our in vitro and in vivo results show that Os-pep has good safety and neuroprotection profiles and crosses the blood-brain barrier. We found reduced levels of neuronal AdipoR1 in human AD brain tissue. Os-pep stimulates AdipoR1 and its downstream target, AMP-activated protein kinase (AMPK) signaling, in AD and Adipo-/- mice. Mechanistically, in all of the in vivo and in vitro studies, Os-pep rescued aberrant neuronal metabolism by reducing neuronal insulin resistance and activated downstream insulin signaling through regulation of AdipoR1/AMPK signaling to consequently improve the memory functions of the AD and Adipo-/- mice, which was associated with improved synaptic function and long-term potentiation via an AdipoR1-dependent mechanism. CONCLUSION: Our findings show that Os-pep activates AdipoR1/AMPK signaling and regulates neuronal insulin resistance and insulin signaling, which subsequently rescues memory deficits in AD and adiponectin-deficient models. Taken together, the results indicate that Os-pep, as an adiponectin-mimetic novel nonapeptide, is a valuable and promising potential therapeutic candidate to treat aberrant brain metabolism associated with AD and other neurodegenerative diseases.
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AMPK activation leads to increased glucose uptake via translocation of GLUT4 to the plasma membrane through a partially insulin-independent mechanism.
“The activation of AMPK leads to acute metabolic responses, such as increased glucose uptake via the translocation of GLUT4 to the plasma membrane, through a partially insulin-independent mechanism”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [86]
The Discussion (page not provided) says activated AMPK regulates brain metabolism and reduces insulin resistance. The Results (page not provided) link AMPK activation to downstream insulin signaling. Neither passage supports increased glucose uptake through GLUT4 translocation or describes that response as partially insulin-independent. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAdiponectin binding to AdipoR1, predominantly expressed in skeletal muscle, activates an intracellular signaling cascade involving AMPK and p38 MAPK.
“Through binding to its specific receptor (AdipoR1), which is predominantly expressed in skeletal muscle, adiponectin activates an intracellular signaling cascade involving AMPK and the p38 MAPK pathway”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [86]
The Background and Discussion describe adiponectin signaling through AdipoR1 and activation of downstream AMPK. Our copy does not establish that AdipoR1 is predominantly expressed in skeletal muscle or that this signaling cascade involves p38 MAPK; the paper discusses neuronal signaling instead. The indexed passages have no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAMPK initiates longer-term adaptations including increased FA oxidation through upregulation of mitochondrial enzymes involved in β-oxidation.
“In parallel, AMPK also initiates longer-term adaptations, including increased FA oxidation through the upregulation of the mitochondrial enzymes involved in β-oxidation”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [86]
The Discussion describes AMPK as an energy sensor that regulates brain metabolism and insulin resistance, but it does not address longer-term adaptations or fatty-acid β-oxidation. Searches for mitochondrial β-oxidation enzymes and increased FA oxidation found no passage supporting the claimed mechanism. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe p38 MAPK pathway contributes primarily to chronic effects, supporting transcriptional activation of genes involved in mitochondrial biogenesis and metabolic remodeling in response to sustained physical activity.
“The p38 MAPK pathway contributes primarily to these chronic effects, supporting the transcriptional activation of the genes involved in mitochondrial biogenesis and metabolic remodeling in response to sustained physical activity”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [86]
The Discussion passages address AdipoR1/AMPK signaling and neuronal insulin resistance in Alzheimer’s disease, not p38 MAPK in response to physical activity. Searches for p38 MAPK, mitochondrial biogenesis, and sustained physical activity found no passage in our copy supporting the attributed claim. (LLM, conf=0.77)
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References 74 · Cited by 65
- Authors
- Ali, T., Rehman, S. U., Khan, A., Badshah, H., Abid, N. B., Kim, M. W., Jo, M. H., Chung, S. S., Lee, H.-G., Rutten, B. P. F., & Kim, M. O.
- Affiliations
- Gyeongsang National University (KR)
- Yonsei University (KR)
- The University of Texas at San Antonio (US)
- Maastricht University Medical Centre (NL)
- Corresponding author
- Kim, Myeong Ok
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2021-04-13
- Volume
- 16
- Issue
- 1
- Pages
- 23-23
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC8042910
- OpenAlex
- W3156451771
- Cited by
- 65
- References
- 74
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 16 · 2023: 12 · 2022: 11 · 2021: 7
- FWCI
- 7.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- National Research Foundation of Korea (2016M3C7A1904391, 2020M3E5D9080660)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- adiponectin, AdipoR1, Alzheimer's disease, AMPK signaling, insulin signaling, memory impairment, synaptic function, long-term potentiation, neuroprotection, blood-brain barrier, APP/PS1 mice, SH-SY5Y cells
- MeSH terms
- Alzheimer Disease, Animals, Drug Evaluation, Preclinical, Humans, Insulin Resistance, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Signal Transduction, Amyloid beta-Peptides, Mice, Knockout, Neuroprotective Agents, Maze Learning, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Mice, Adiponectin, Presenilin-1, Receptors, Adiponectin, AMP-Activated Protein Kinases
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