Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease
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Reduced spine densities and age‐dependent accumulation of amyloid β and tau pathology are shared features of Down syndrome (DS) and Alzheimer's disease (AD). Both spine morphology and the synaptic plasticity that supports learning depend upon the actin cytoskeleton, suggesting that disturbances in actin regulatory signaling might underlie spine defects in both disorders. The present study evaluated the synaptic levels of two proteins that promote filamentous actin stabilization, the Rho GTPase effector p21‐activated kinase 3 (PAK3) and Arp2, in DS vs. AD. Fluorescent deconvolution tomography was used to determine postsynaptic PAK3 and Arp2 levels for large numbers of excitatory synapses in the parietal cortex of individuals with DS plus AD pathology (DS + AD) or AD alone relative to age‐matched controls. Though numbers of excitatory synapses were not different between groups, synaptic PAK3 levels were greatly reduced in DS + AD and AD individuals vs. controls. Synaptic Arp2 levels also were reduced in both disorders, but to a greater degree in AD. Western blotting detected reduced Arp2 levels in the AD group, but there was no correlation with phosphorylated tau levels suggesting that the Arp2 loss does not contribute to mechanisms that drive tau pathology progression. Overall, the results demonstrate marked synaptic disturbances in two actin regulatory proteins in adult DS and AD brains, with greater effects in individuals with AD alone. As both PAK and the Arp2/3 complex play roles in the actin stabilization that supports synaptic plasticity, reductions in these proteins at synapses may be early events in spine dysfunction that contribute to cognitive impairment in these disorders.
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An overall reduction in ARP2 has been found in human AD parietal cortex tissue.
“In the context of AD, an overall reduction in ARP2 has been found in human AD parietal cortex tissue [51].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [51]
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DiFilippo, A. H., Jonaitis, E. M., Makuch, R., Piro‐Gambetti, B., Fleming, V., Ennis, G. E., Barnhart, T. E., Engle, J. W., Bendlin, B. B., Johnson, S. C., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-54669-7 · Cited by 7 · see citing works
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The Evaluation of Rac1 Signaling as a Potential Therapeutic Target of Alzheimer’s Disease
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RetractedRETRACTED: PAK3 downregulation induces cognitive impairment following cranial irradiation
Lee, H., Kang, H., Moon, C., & Youn, B. (2023) · eLife · doi:10.7554/elife.89221.3 · Cited by 3 · see citing works
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PAK3 downregulation induces cognitive impairment following cranial irradiationPreprint
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RETRACTED: PAK3 downregulation induces cognitive impairment following cranial irradiationPreprint
Lee, H., Kang, H., Moon, C., & Youn, B. (2023) · eLife · doi:10.7554/elife.89221.1
RetractedLee, H., Kang, H., Moon, C., et al. (2023) · eLife · doi:10.7554/elife.89221.1.sa0
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PAK3 downregulation induces cognitive impairment following cranial irradiationPreprint
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- Authors
- Lauterborn, J. C., Cox, C. D., Chan, S. W., Vanderklish, P. W., Lynch, G., & Gall, C. M.
- Affiliations
- University of California, Irvine (US)
- Scripps Research Institute (US)
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2019-09-08
- Volume
- 30
- Issue
- 2
- Pages
- 319-331
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC7015764
- OpenAlex
- W2968516410
- Cited by
- 43
- References
- 64
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 8 · 2023: 18 · 2022: 2 · 2021: 7 · 2020: 4 · 2017: 1
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (AG00096‐34, AG016573)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD079823, HD089491)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Down syndrome, Alzheimer's disease, Arp2, Arp2/3 complex, dendritic spine density, actin cytoskeleton, synaptic plasticity, amyloid-beta, tau pathology, parietal cortex, cognitive impairment
- MeSH terms
- Actins, Alzheimer Disease, Down Syndrome, Female, Humans, Male, Middle Aged, Synapses, Actin-Related Protein 2, p21-Activated Kinases
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