Reduction of Synaptojanin 1 Accelerates Aβ Clearance and Attenuates Cognitive Deterioration in an Alzheimer Mouse Model
Open accessAbstract
Recent studies link synaptojanin 1 (synj1), the main phosphoinositol (4,5)-biphosphate phosphatase (PI(4,5)P2-degrading enzyme) in the brain and synapses, to Alzheimer disease. Here we report a novel mechanism by which synj1 reversely regulates cellular clearance of amyloid-β (Aβ). Genetic down-regulation of synj1 reduces both extracellular and intracellular Aβ levels in N2a cells stably expressing the Swedish mutant of amyloid precursor protein (APP). Moreover, synj1 haploinsufficiency in an Alzheimer disease transgenic mouse model expressing the Swedish mutant APP and the presenilin-1 mutant ΔE9 reduces amyloid plaque load, as well as Aβ40 and Aβ42 levels in hippocampus of 9-month-old animals. Reduced expression of synj1 attenuates cognitive deficits in these transgenic mice. However, reduction of synj1 does not affect levels of full-length APP and the C-terminal fragment, suggesting that Aβ generation by β- and γ-secretase cleavage is not affected. Instead, synj1 knockdown increases Aβ uptake and cellular degradation through accelerated delivery to lysosomes. These effects are partially dependent upon elevated PI(4,5)P2 with synj1 down-regulation. In summary, our data suggest a novel mechanism by which reduction of a PI(4,5)P2-degrading enzyme, synj1, improves amyloid-induced neuropathology and behavior deficits through accelerating cellular Aβ clearance. Background: Recent studies have linked synaptojanin 1 (synj1) with Alzheimer disease (AD). Results: We report that synj1 reduction decreases amyloid plaque burden and attenuates cognitive deterioration in an AD mouse model. These effects are mediated through accelerating endosomal/lysosomal degradation of Aβ. Conclusion: Our data suggest a novel mechanism by which synj1 reduction promotes Aβ clearance. Significance: These studies implicate a therapeutic strategy for AD.
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DS mouse models show disrupted PI(4,5)P2 metabolism caused by an extra copy of Synj1.
“DS mouse models show disrupted PI(4,5)P2 metabolism that is caused by an extra copy of Synj1 [96, 97].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [96]
The Knockdown of synj1 section reports that reducing Synj1 raises PIP2, which consists mostly of PI(4,5)P2, in Alzheimer-model mice. That supports the link between Synj1 dosage and PI(4,5)P2 levels, but the non-abstract passages do not establish the claimed disruption in Down syndrome mouse models. (LLM, conf=0.78)
Experimental — accuracy not yet measuredSYNJ1 is on chromosome 21 and is elevated in Down syndrome brains.
“SYNJ1 is on chromosome 21 and is elevated in Down syndrome (DS) brains.”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [96]
The Abstract (page unavailable) reports trisomy of synj1 in Down syndrome mouse models, supporting a connection between SYNJ1 dosage and Down syndrome. It does not state that SYNJ1 is on chromosome 21 or that its levels are elevated in human Down syndrome brains. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe C-terminus of SHIP1 contains a NPxY motif that can bind proteins containing ITIM/ITAM, PTB or SH2 domains, and a proline-rich PxxP motif that contains SH3-binding domains.
“The C-terminus of SHIP1 contains a NPxY motif, which can bind to proteins containing immunoreceptor tyrosine inhibitory motifs (ITIM)/immunoreceptor tyrosine activating motifs (ITAM), phosphotyrosine-binding (PTB) or SH2 domains, as well as a proline-rich PxxP motif that contains SH3-binding domains [47, 93–98] (Fig. 2).”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [96]
The Experimental Procedures and Discussion passages concern synaptojanin 1, amyloid-β clearance, and endosomal trafficking; page numbers are unavailable in our copy. Searches for SHIP1, NPxY, PxxP, and the named binding domains found no passage addressing the claimed SHIP1 motifs or interactions. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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References 50 · Cited by 70
Research works printed but not linked: 6
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- Authors
- Zhu, L., Zhong, M., Zhao, J., Rhee, H., Caesar, I., Knight, E. M., Volpicelli-Daley, L., Bustos, V., Netzer, W., Liu, L., Lucast, L., Ehrlich, M. E., Robakis, N. K., Gandy, S. E., & Cai, D.
- Affiliations
- James J. Peters VA Medical Center (US)
- New York Medical College (US)
- Rockefeller University (US)
- Yale University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Cai, Dongming
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 288
- Issue
- 44
- Pages
- 32050-32063
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3814799
- OpenAlex
- W2045060921
- Cited by
- 70
- References
- 50
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 8 · 2021: 8 · 2020: 10 · 2019: 9 · 2018: 7 · 2017: 4 · 2016: 5 · 2015: 7 · 2014: 4
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Funders
- National Science Foundation (9724504)
- Yale University
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health (1s10rr009145-01)
- National Cancer Institute (R24CA095823)
- National Institute of Neurological Disorders and Stroke (NS 047229, R01NS047229)
- National Center for Research Resources (S10 RR0 9145-01)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- SYNJ1, Alzheimer's disease, amyloid-beta clearance, phosphatidylinositol 4,5-bisphosphate, lysosomal degradation, endosomal trafficking, amyloid plaques, cognitive impairment, amyloid precursor protein, therapeutic target
- MeSH terms
- Phosphoinositide 5-Phosphatases, Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Humans, Lysosomes, Mice, Transgenic, Mutation, Peptide Fragments, Phosphoric Monoester Hydrolases, Down-Regulation, Amyloid beta-Peptides, Phosphatidylinositol 4,5-Diphosphate, Cell Line, Tumor, Mice, Presenilin-1, Amyloid Precursor Protein Secretases, Gene Knockdown Techniques
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