Pyk2 Signaling through Graf1 and RhoA GTPase Is Required for Amyloid-β Oligomer-Triggered Synapse Loss
Open accessAbstract
The intracellular tyrosine kinase Pyk2 (PTK2B) is related to focal adhesion kinase and localizes to postsynaptic sites in brain. Pyk2 genetic variation contributes to late onset Alzheimer's disease (AD) risk. We recently observed that Pyk2 is required for synapse loss and for learning deficits in a transgenic mouse model of AD. Here, we explore the cellular and biochemical basis for the action of Pyk2 tyrosine kinase in amyloid-β oligomer (Aβo)-induced dendritic spine loss. Overexpression of Pyk2 reduces dendritic spine density of hippocampal neurons by a kinase-dependent mechanism. Biochemical isolation of Pyk2-interacting proteins from brain identifies Graf1c, a RhoA GTPase-activating protein inhibited by Pyk2. Aβo-induced reductions in dendritic spine motility and chronic spine loss require both Pyk2 kinase and RhoA activation. Thus, Pyk2 functions at postsynaptic sites to modulate F-actin control by RhoA and regulate synapse maintenance of relevance to AD risk. SIGNIFICANCE STATEMENT Genetic variation at the Pyk2 locus is a risk for Alzheimer's disease. We have observed that Pyk2 is required for AD transgenic synapse loss and memory dysfunction. However, the cellular and biochemical basis for Pyk2 function related to AD is not defined. Here, we show that brain Pyk2 interacts with the RhoGAP protein Graf1 to alter dendritic spine stability via RhoA GTPase. Amyloid-β oligomer-induced dendritic spine loss requires the Pyk2/Graf1 pathway.
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Oligomeric Aβ induces synaptic loss in neurons via Pyk2-mediated inactivation of the RhoGAP Graf1, leading to RhoA activation and subsequent dendritic spine retraction.
“Oligomeric Aβ was found to induce synaptic loss in neurons via Pyk2-mediated inactivation of the RhoGAP Graf1, leading to RhoA activation and subsequent dendritic spine retraction [193].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [193]
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Research works printed but not linked: 1
- Salazar SV, Cox TO, Lee S, Brody AH, Chyung AS, Haas LT, Strittmatter SM (2018) Alzheimer's disease risk factor Pyk2 mediates amyloid--induced synaptic dysfunction and loss. J Neurosci. Advance online publication. Retrieved December 5, 2018. doi: 10.1523/JNEUROSCI.1873-18.2018. · DOI · Paper page
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RhoA Signaling in Neurodegenerative Diseases
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The role of genetic risk factors of Alzheimer’s disease in synaptic dysfunction
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- Authors
- Lee, S., Salazar, S. V., Cox, T. O., & Strittmatter, S. M.
- Affiliations
- Yale University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2019-01-09
- Volume
- 39
- Issue
- 10
- Pages
- 1910-1929
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6407289
- OpenAlex
- W2909808142
- Cited by
- 55
- References
- 9
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 4 · 2023: 7 · 2022: 10 · 2021: 8 · 2020: 11 · 2019: 1
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (RF1AG053000, P50AG047270, R01AG034924)
- National Institute of Neurological Disorders and Stroke (R35NS097283)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Pyk2, RhoA, amyloid-beta oligomers, dendritic spine loss, synaptic loss, Alzheimer's disease, RhoGAP, postsynaptic signaling, hippocampal neurons, tyrosine kinase
- MeSH terms
- Animals, Female, Hippocampus, Humans, Male, Mice, Inbred C57BL, Synapses, Signal Transduction, Amyloid beta-Peptides, Mice, Knockout, GTPase-Activating Proteins, rhoA GTP-Binding Protein, Dendritic Spines, Focal Adhesion Kinase 2, HEK293 Cells
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