PMID- 33849621 OWN - NLM STAT- MEDLINE DCOM- 20211215 LR - 20211215 IS - 1750-1326 (Electronic) IS - 1750-1326 (Linking) VI - 16 IP - 1 DP - 2021 Apr 13 TI - Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer's disease. PG - 23 LID - 10.1186/s13024-021-00445-4 [doi] LID - 23 AB - 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 mug/g, i.p., on alternating days for 45 days) for APP/PS1 in amyloid beta 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. FAU - Ali, Tahir AU - Ali T AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Rehman, Shafiq Ur AU - Rehman SU AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Khan, Amjad AU - Khan A AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Badshah, Haroon AU - Badshah H AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Abid, Noman Bin AU - Abid NB AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Kim, Min Woo AU - Kim MW AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Jo, Myeung Hoon AU - Jo MH AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Chung, Seung Soo AU - Chung SS AD - Department of Physiology, College of Medicine, Yonsei University, Seoul, 120-752, Republic of Korea. FAU - Lee, Hyoung-Gon AU - Lee HG AD - Department of Biology, The University of Texas at San Antonio, San Antonio, USA. FAU - Rutten, Bart P F AU - Rutten BPF AD - Translational Neuroscience and Psychiatry, School for Mental Health and Neuroscience (MHeNs), Maastricht University Medical Centre, Maastricht, Netherlands. FAU - Kim, Myeong Ok AU - Kim MO AUID- ORCID: 0000-0003-4317-1072 AD - Division of Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. mokim@gnu.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210413 PL - England TA - Mol Neurodegener JT - Molecular neurodegeneration JID - 101266600 RN - 0 (ADIPOQ protein, human) RN - 0 (ADIPOR1 protein, human) RN - 0 (Adiponectin) RN - 0 (Adipoq protein, mouse) RN - 0 (Amyloid beta-Peptides) RN - 0 (Neuroprotective Agents) RN - 0 (PSEN1 protein, human) RN - 0 (Presenilin-1) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Adiponectin) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Adiponectin/deficiency MH - Alzheimer Disease/*drug therapy/metabolism/psychology MH - Amyloid beta-Peptides/genetics MH - Animals MH - Cell Line, Tumor MH - Drug Evaluation, Preclinical MH - Humans MH - Insulin Resistance MH - Male MH - Maze Learning MH - Memory Disorders/drug therapy/etiology/*prevention & control MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Neurons/drug effects MH - Neuroprotective Agents/*pharmacology/therapeutic use MH - Presenilin-1/genetics MH - RNA Interference MH - RNA, Small Interfering/genetics MH - Receptors, Adiponectin/*antagonists & inhibitors/genetics MH - Signal Transduction PMC - PMC8042910 OTO - NOTNLM OT - AdipoR1/AMPK signaling OT - Adiponectin-mimetic novel nonapeptide (Os-pep) OT - Alzheimer's disease (AD) OT - Brain metabolic disorders OT - Insulin signaling OT - Neuronal adiponectin receptor 1 (AdipoR1) OT - Neuronal insulin resistance OT - Synaptic and memory deficits COIS- The authors declare no competing financial interest. EDAT- 2021/04/15 06:00 MHDA- 2021/12/16 06:00 PMCR- 2021/04/13 CRDT- 2021/04/14 05:41 PHST- 2020/04/24 00:00 [received] PHST- 2021/03/24 00:00 [accepted] PHST- 2021/04/14 05:41 [entrez] PHST- 2021/04/15 06:00 [pubmed] PHST- 2021/12/16 06:00 [medline] PHST- 2021/04/13 00:00 [pmc-release] AID - 10.1186/s13024-021-00445-4 [pii] AID - 445 [pii] AID - 10.1186/s13024-021-00445-4 [doi] PST - epublish SO - Mol Neurodegener. 2021 Apr 13;16(1):23. doi: 10.1186/s13024-021-00445-4.