The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation
Open accessAbstract
Amyloid-β 1-42 (Aβ42) oligomers are synaptotoxic for excitatory cortical and hippocampal neurons and might play a role in early stages of Alzheimer's disease (AD) progression. Recent results suggested that Aβ42 oligomers trigger activation of AMP-activated kinase (AMPK), and its activation is increased in the brain of patients with AD. We show that increased intracellular calcium [Ca²⁺](i) induced by NMDA receptor activation or membrane depolarization activates AMPK in a CAMKK2-dependent manner. CAMKK2 or AMPK overactivation is sufficient to induce dendritic spine loss. Conversely, inhibiting their activity protects hippocampal neurons against synaptotoxic effects of Aβ42 oligomers in vitro and against the loss of dendritic spines observed in the human APP(SWE,IND)-expressing transgenic mouse model in vivo. AMPK phosphorylates Tau on KxGS motif S262, and expression of Tau S262A inhibits the synaptotoxic effects of Aβ42 oligomers. Our results identify a CAMKK2-AMPK-Tau pathway as a critical mediator of the synaptotoxic effects of Aβ42 oligomers.
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Aβ-induced dendritic spine loss and neuronal death depend on Tau phosphorylation.
“Aβ-induced dendritic spine loss [88] and neuronal death [130] depend on Tau phosphorylation.”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [88]
Studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity depends on tau phosphorylation at these sites.
“Notably, studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity caused by Aβ depends on tau phosphorylation at these sites [39, 45, 56–58].”
During aging, impaired proteostasis and energy production plus increased oxidative damage compromise subcellular Ca2+ handling, which may lead to caspase-regulated apoptosis and PARP1-mediated neuronal death.
“During aging, the neurons suffer impaired proteostasis and energy production as well as increased oxidative damage, resulting in compromised subcellular Ca2+ handling, which may lead to caspase-regulated apoptosis and PARP1-mediated neuronal death (Bezprozvanny and Mattson, 2008; Mairet-Coello et al., 2013).”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Mairet-Coello et al., 2013
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- Authors
- Mairet-Coello, G., Courchet, J., Pieraut, S., Courchet, V., Maximov, A., & Polleux, F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Polleux, Franck
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 78
- Issue
- 1
- Pages
- 94-108
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3784324
- OpenAlex
- W2088148170
- Cited by
- 351
- References
- 91
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 18 · 2023: 20 · 2022: 27 · 2021: 37 · 2020: 24 · 2019: 26 · 2018: 31 · 2017: 36 · 2016: 33 · 2015: 21 · 2014: 26 · 2013: 12
- FWCI
- 21.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Columbia Academic Commons (Columbia University)
- Funders
- National Institute on Aging (R01AG031524)
- National Institute of Mental Health (R01MH085776)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta oligomers, CAMKK2, AMPK, tau phosphorylation, synaptotoxicity, dendritic spine loss, NMDA receptor activation, intracellular calcium, Alzheimer's disease, hippocampal neurons
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Action Potentials, Animals, Brain, Calcium, Cells, Cultured, Dose-Response Relationship, Drug, Embryo, Mammalian, Enzyme Inhibitors, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neurons, Peptide Fragments, Phosphorylation, Platelet-Derived Growth Factor, Protein Kinases, Serine, Transfection, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Electroporation, Patch-Clamp Techniques, Glutamic Acid, Dendritic Spines, Green Fluorescent Proteins, Mice, Calcium-Calmodulin-Dependent Protein Kinase Kinase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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