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Article: Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer’s disease mouse model

TitleChronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer’s disease mouse model
Authors
KeywordsINSULIN-RESISTANCE
POSSIBLE INVOLVEMENT
BETA DEPOSITION
DENTATE GYRUS
ADIPONECTIN
Issue Date2020
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/mp
Citation
Molecular Psychiatry, 2020, Epub 2020-03-04 How to Cite?
AbstractCirculating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN−/−) mice developed Alzheimer’s like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer’s disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN−/− mice to generate APN-deficient 5xFAD (5xFAD;APN−/−). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood–brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN−/− mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.
Persistent Identifierhttp://hdl.handle.net/10722/281690
ISSN
2019 Impact Factor: 12.384
2015 SCImago Journal Rankings: 6.790
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNg, RC-L-
dc.contributor.authorJIAN, M-
dc.contributor.authorMa, OK-F-
dc.contributor.authorBunting, M-
dc.contributor.authorKwan, JS-C-
dc.contributor.authorZhou, G-J-
dc.contributor.authorSenthilkumar, K-
dc.contributor.authorIyaswamy, A-
dc.contributor.authorChan, P-K-
dc.contributor.authorLi, M-
dc.contributor.authorLeung, KM-Y-
dc.contributor.authorKumar Durairajan, S-S-
dc.contributor.authorLam, KS-L-
dc.contributor.authorChu, L-W-
dc.contributor.authorFestenstein, R-
dc.contributor.authorChung, SK-
dc.contributor.authorChan, K-H-
dc.date.accessioned2020-03-22T04:18:21Z-
dc.date.available2020-03-22T04:18:21Z-
dc.date.issued2020-
dc.identifier.citationMolecular Psychiatry, 2020, Epub 2020-03-04-
dc.identifier.issn1359-4184-
dc.identifier.urihttp://hdl.handle.net/10722/281690-
dc.description.abstractCirculating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN−/−) mice developed Alzheimer’s like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer’s disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN−/− mice to generate APN-deficient 5xFAD (5xFAD;APN−/−). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood–brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN−/− mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.-
dc.languageeng-
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/mp-
dc.relation.ispartofMolecular Psychiatry-
dc.rightsThis is a post-peer-review, pre-copyedit version of an article published in [insert journal title]. The final authenticated version is available online at: https://doi.org/[insert DOI]-
dc.subjectINSULIN-RESISTANCE-
dc.subjectPOSSIBLE INVOLVEMENT-
dc.subjectBETA DEPOSITION-
dc.subjectDENTATE GYRUS-
dc.subjectADIPONECTIN-
dc.titleChronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer’s disease mouse model-
dc.typeArticle-
dc.identifier.emailNg, RC-L: royclng@hku.hk-
dc.identifier.emailMa, OK-F: oscarmkf@hku.hk-
dc.identifier.emailKwan, JS-C: jsckwan@hku.hk-
dc.identifier.emailZhou, G-J: zhougj@hku.hk-
dc.identifier.emailLeung, KM-Y: kmyleung@hku.hk-
dc.identifier.emailLam, KS-L: ksllam@hku.hk-
dc.identifier.emailChu, L-W: lwchu@hkucc.hku.hk-
dc.identifier.emailChan, K-H: koonho@hku.hk-
dc.identifier.authorityNg, RC-L=rp02376-
dc.identifier.authorityLeung, KM-Y=rp00733-
dc.identifier.authorityLam, KS-L=rp00343-
dc.identifier.authorityChung, SK=rp00381-
dc.identifier.authorityChan, K-H=rp00537-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41380-020-0701-0-
dc.identifier.hkuros309474-
dc.identifier.volumeEpub 2020-03-04-
dc.identifier.isiWOS:000518096200001-
dc.publisher.placeUnited Kingdom-

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