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AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model.

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Τίτλος: AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model.
Συγγραφείς: Nicol NI; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Li T; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Su Q; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Suhocki A; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Dunlap E; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Zhou X; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Jester HM; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Swift NA; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Underwood E; Department of Internal Medicine-Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Lee J; Department of Internal Medicine-Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Cervera-Juanes R; Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA., Ma T; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.; Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Πηγή: Journal of neurochemistry [J Neurochem] 2026 Oct; Vol. 170 (10), pp. e70563.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Wiley on behalf of the International Society for Neurochemistry Country of Publication: England NLM ID: 2985190R Publication Model: Print Cited Medium: Internet ISSN: 1471-4159 (Electronic) Linking ISSN: 00223042 NLM ISO Abbreviation: J Neurochem Subsets: MEDLINE
Imprint Name(s): Publication: 2001- : Oxford, UK : Wiley on behalf of the International Society for Neurochemistry
Original Publication: New York : Raven Press
Ιατρικοί όροι (MeSH): Alzheimer Disease*/drug therapy , Alzheimer Disease*/metabolism , Alzheimer Disease*/genetics , Metabolome*/drug effects , Metabolome*/physiology , AMP-Activated Protein Kinases*/metabolism , Amyloid beta-Protein Precursor*/genetics , Memory Disorders*/drug therapy , Memory Disorders*/metabolism , Memory Disorders*/genetics , Spatial Memory*/drug effects , Spatial Memory*/physiology, Presenilin-1/genetics ; Hippocampus/drug effects ; Hippocampus/metabolism ; Animals ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Male
Περίληψη: Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6-8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.
(© 2026 International Society for Neurochemistry.)
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Grant Information: R01 AG073823 United States AG NIA NIH HHS; R01 AG082388 United States AG NIA NIH HHS; RF1 AG082388 United States AG NIA NIH HHS
Contributed Indexing: Keywords: AMPK; AMPK activation; Alzheimer's disease; LTP; memory; metabolome
Substance Nomenclature: EC 2.7.11.31 (AMP-Activated Protein Kinases)
0 (Presenilin-1)
0 (Amyloid beta-Protein Precursor)
Entry Date(s): Date Created: 20261002 Date Completed: 20261002 Latest Revision: 20261004
Update Code: 20261004
DOI: 10.1111/jnc.70563
PMID: 42825521
Βάση Δεδομένων: MEDLINE
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Items – Name: Title
  Label: Title
  Group: Ti
  Data: AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AU" term="%22Nicol+NI%22">Nicol NI</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Li+T%22">Li T</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Su+Q%22">Su Q</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Suhocki+A%22">Suhocki A</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Dunlap+E%22">Dunlap E</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Zhou+X%22">Zhou X</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Jester+HM%22">Jester HM</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Swift+NA%22">Swift NA</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Underwood+E%22">Underwood E</searchLink>; Department of Internal Medicine-Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Lee+J%22">Lee J</searchLink>; Department of Internal Medicine-Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Cervera-Juanes+R%22">Cervera-Juanes R</searchLink>; Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.<br /><searchLink fieldCode="AU" term="%22Ma+T%22">Ma T</searchLink>; Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.; Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
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  Data: <searchLink fieldCode="JN" term="%222985190R%22">Journal of neurochemistry</searchLink> [J Neurochem] 2026 Oct; Vol. 170 (10), pp. e70563.
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  Data: Journal Article
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  Label: Language
  Group: Lang
  Data: English
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Wiley+on+behalf+of+the+International+Society+for+Neurochemistry%22">Wiley on behalf of the International Society for Neurochemistry </searchLink><i>Country of Publication: </i>England <i>NLM ID: </i>2985190R <i>Publication Model: </i>Print <i>Cited Medium: </i>Internet <i>ISSN: </i>1471-4159 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2200223042%22">00223042 </searchLink><i>NLM ISO Abbreviation: </i>J Neurochem <i>Subsets: </i>MEDLINE
– Name: PublisherInfo
  Label: Imprint Name(s)
  Group: PubInfo
  Data: <i>Publication</i>: 2001- : Oxford, UK : Wiley on behalf of the International Society for Neurochemistry<br /><i>Original Publication</i>: New York : Raven Press
– Name: SubjectMESH
  Label: MeSH Terms
  Group: Su
  Data: <searchLink fieldCode="MM" term="%22Alzheimer+Disease%22">Alzheimer Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Alzheimer+Disease+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Alzheimer+Disease%22">Alzheimer Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Alzheimer+Disease+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Alzheimer+Disease%22">Alzheimer Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Alzheimer+Disease+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Metabolome%22">Metabolome*</searchLink>/<searchLink fieldCode="MM" term="%22Metabolome+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Metabolome%22">Metabolome*</searchLink>/<searchLink fieldCode="MM" term="%22Metabolome+physiology%22">physiology</searchLink> <br /><searchLink fieldCode="MM" term="%22AMP-Activated+Protein+Kinases%22">AMP-Activated Protein Kinases*</searchLink>/<searchLink fieldCode="MM" term="%22AMP-Activated+Protein+Kinases+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Amyloid+beta-Protein+Precursor%22">Amyloid beta-Protein Precursor*</searchLink>/<searchLink fieldCode="MM" term="%22Amyloid+beta-Protein+Precursor+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Memory+Disorders%22">Memory Disorders*</searchLink>/<searchLink fieldCode="MM" term="%22Memory+Disorders+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Spatial+Memory%22">Spatial Memory*</searchLink>/<searchLink fieldCode="MM" term="%22Spatial+Memory+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Spatial+Memory%22">Spatial Memory*</searchLink>/<searchLink fieldCode="MM" term="%22Spatial+Memory+physiology%22">physiology</searchLink><br /><searchLink fieldCode="MH" term="%22Presenilin-1%22">Presenilin-1</searchLink>/<searchLink fieldCode="MH" term="%22Presenilin-1+genetics%22">genetics</searchLink> ; <searchLink fieldCode="MH" term="%22Hippocampus%22">Hippocampus</searchLink>/<searchLink fieldCode="MH" term="%22Hippocampus+drug+effects%22">drug effects</searchLink> ; <searchLink fieldCode="MH" term="%22Hippocampus%22">Hippocampus</searchLink>/<searchLink fieldCode="MH" term="%22Hippocampus+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Transgenic%22">Mice, Transgenic</searchLink> ; <searchLink fieldCode="MH" term="%22Disease+Models%2C+Animal%22">Disease Models, Animal</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6-8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.<br /> (© 2026 International Society for Neurochemistry.)
– Name: Ref
  Label: References
  Group: RefInfo
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