Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis
Open accessAbstract
Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the pro-apoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects.
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In healthy neurons, Tau is observed in the dendritic shaft as well as in pre- and post-synaptic structures.
“Interestingly, several recent studies suggest that Tau may directly regulate synaptic function and plasticity: in healthy neurons, Tau is observed in the dendritic shaft as well as in pre- and post-synaptic structures [92, 94, 156].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [156]
The Results section (page unavailable) reports endogenous cleaved tau in dendrites, cleaved tau in synaptosomal and postsynaptic-density fractions, and full-length tau in synaptosomal fractions. It does not establish that tau occupies both pre- and postsynaptic structures in healthy neurons: the synaptosomal fraction is not identified as presynaptic, and relatively little full-length tau was found in the postsynaptic-density fraction. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTau is also present in dendrites and postsynaptic compartments.
“Recent studies demonstrate that tau is also present in dendrites and postsynaptic compartments [128–130].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [130]
Appoptosin overexpression activates caspase-3 and enhances caspase-3 dependent tau cleavage, thereby enhancing motor dysfunction in JNPL3 tau transgenic mice.
“Appoptosin overexpression activates caspase-3 and enhances caspase-3 dependent tau cleavage, thereby enhancing motor dysfunction in JNPL3 tau transgenic mice [130].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [130]
Tau-421 can be found in PSD fractions from primary neuronal cultures.
“In addition, tau-421 can be found in PSD fractions from primary neuronal cultures [130]”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [130]
Caspase-3 cleavage leads to dissociation of tau from microtubules, and enhanced tau aggregation.
“Caspase-3 cleavage leads to the dissociation of tau from microtubules, and enhanced tau aggregation [130, 191, 195].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [130]
Elevated levels of caspase-3 and tau-421 have been observed in AD, as well as PSP.
“Elevated levels of caspase-3 and tau-421 have been observed in AD, as well as PSP [130, 191, 192].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [130]
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“This locus has previously been implicated in differential expression of the SLC25A38/ appoptosin gene, which may regulate tau cleavage [42].”
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MethodSelf-citationHuman Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration
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“Caspase-3 cleavage at D421-S422 results in Tau 1–421 (Tau-C) which is linked to AD and PSP (Gamblin et al., 2003; Zhao et al., 2015).”
BackgroundOrdered Assembly of Tau Protein and Neurodegeneration
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Impact of Tau on Neurovascular Pathology in Alzheimer's Disease
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“Considerable evidence shows that caspase-3-truncated tau species are particularly prone to phosphorylation (65), and that caspase-dependent cleavage process increases tau propensity to self-aggregate, boosting the rate of tau polymerization and NFT assembly (45, 47, 59, 66), and fostering dendritic spine loss, synapti…”
BackgroundGenetics of Progressive Supranuclear Palsy: A Review
Wen, Y., Zhou, Y., Jiao, B., & Shen, L. H. (2020) · Journal of Parkinson s Disease · doi:10.3233/jpd-202302 · Cited by 64 · see citing works
“Surprisingly, the increased representation of rs1768208 with the minor T-allele in PSP cases is more closely linked with the expression of the SLC25A38/Appoptosin gene, though its location is nearer to the myelin-associated oligodendrocyte basic protein (MOBP) gene [19, 105].”
BackgroundThe ordered assembly of tau is the gain‐of‐toxic function that causes human tauopathies
Goedert, M. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.09.001 · Cited by 62 · see citing works
“For PSP and CBD, an association has also been found with an allele at the MOBP/SLC25A38 locus, which results in elevated levels of appoptosin, a protein that activates caspase-3, which can cleave tau [74].”
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“In turn, a recent study based on progressive supranuclear palsy showed a close relationship between Appoptosin (a mitochondrial protein), caspase 3 activation, and truncated tau generation [68].”
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“to procedures previously reported [32, 33].”
Self-citationTargeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression
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“…its role in SLC25A38/Apoptosin gene locus 70kbp away, we did observe a signal in oligodendrocyte single cell data as well as downregulation of expression in PSP brains in addition to fi ne mapping oligodendrocytic enhancers and promoters as well as an observed signal in the MPRA data 22,35 .”
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“Increased protein level of appoptosin has been observed in frontal cortical tissues of AD patients and appoptosin-mediated caspase cleavage of tau aggravates tau pathology (Zhao et al., 2015).”
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“Tau truncation can take place at N-terminal or C-terminal regions [6, 22, 41, 44, 46, 48, 52, 63, 64].”
BackgroundProgressive supranuclear palsy
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“GSK3 phosphorylates tau at specific serine residues, decreases its affinity for MTs and enhances its folding into paired helical filaments and forming intracellular aggregates.”
BackgroundInfluentialGenetic Architecture of Primary Tauopathies
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“The effect of this SNP on appoptosin was subsequently confirmed, and it was further shown that elevated appoptosin levels can induce tau-associated neurodegeneration by promoting tau cleavage by caspace-3 activation.(39) Similarly, PERK participates in the cellular response to misfolded proteins (unfolded protein resp…”
BackgroundDisease-modifying strategies in primary tauopathies
Rösler, T. W., Costa, M., & Höglinger, G. U. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107842 · Cited by 14 · see citing works
Appoptosin Mediates Lesions Induced by Oxidative Stress Through the JNK-FoxO1 Pathway
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“An SNP (rs1768208, C/T) associated with progressive supranuclear palsy is located near the MOB gene on chromosome 3 and is correlated with increased expression of Appoptosin, whose gene is approximately 70 kb apart from MOB [53].”
BackgroundRizzi, L., & Grinberg, L. T. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01744-9 · Cited by 11 · see citing works
“In PSP, appotosin, a mitochondrial carrier protein, activates caspase-3 and mediates tau cleavage at Asp421 [65].”
BackgroundDu, Y., Guo, T., Hao, Y., Li, C., Tang, L., Li, X., Zhang, X., Li, L., Yao, D., Xu, X., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14047 · Cited by 11 · see citing works
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Self-citationRetromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau
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“Caspase-3 cleavage of tau increases with age and may contribute to neurodegeneration (Zhang et al., 2009; Zhao et al., 2015).”
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“…is approved and used for the treatment of cerebral vasospasm in Japan and China (Hamano et al., 2020; Couch et al., 2010; Ono-Saito et al., 1999; Zhao et al., 2015; Guo et al., 2019), and is currently in clinical trials for tauopathies of Progressive Supranuclear Palsy-Richardson Syndrome and…”
Dynamics of microtubules and their associated proteins
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“dissociate from microtubules and aggregate.(67) Chronic traumatic encephalopathy is associated with accumulation of toxic cis-form of tau phosphorylated at residue 231 (cis p-tau); in experimental models, this process, called cistauosis, is associated with microtubule disassembly, impaired axonal transport, and spread…”
BackgroundAlzheimer’s Disease-Related Cerebrospinal Fluid Biomarkers in Progressive Supranuclear Palsy
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Increased level of RAB39B leads to neuronal dysfunction and behavioural changes in mice
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Therapeutic options for Progressive Supranuclear Palsy including investigational drugs
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“Despite recent advances in understanding of pathogenesis of PSP as a tauopathy [20,21], there are only a few doubleblind, placebo, controlled trials that determined the efficacy of disease-modifying or pharmacological therapies for PSP patients.”
BackgroundPotential role of Drug Repositioning Strategy (DRS) for management of tauopathy
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“Tau is also present in dendrites and postsynaptic compartments where regulates synaptic plasticity [164–166].”
Overexpression of appoptosin promotes mitochondrial damage in MIN6 cells
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“This observation agrees with other studies showing the infrequent presence of Tau-D421 positive neurofilamentous tau aggregates in AD, familial FTLD-Tau [57–59], and in PSP brain neurons [60].”
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Tau in Tauopathies That Leads to Cognitive Disorders and in Cancer
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Mechanistic Insight into Tau Fibril Cross-Seeding Barriers: Structural Order and Disorder
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In memoriam of Huaxi Xu, PhD, 1964–2022
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“J In contrast, MAPT and SNCA downregulation reduced cytotoxicity; this intervention likely prevents caspase activation and its downstream apoptotic effects [60].”
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The Cognitive Neurology of Corticobasal Degeneration and Progressive Supranuclear Palsy
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Tau Protein in Alzheimer's Disease
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- Authors
- Zhao, Y., Tseng, I.-C., Heyser, C. J., Rockenstein, E., Mante, M., Adame, A., Zheng, Q., Huang, T., Wang, X., Arslan, P. E., Chakrabarty, P., Wu, C., Bu, G., Mobley, W. C., Zhang, Y.-W., St. George-Hyslop, P., Masliah, E., Fraser, P., & Xu, H.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of California San Diego (US)
- Xiamen University (CN)
- University of Florida (US)
- University of Toronto (CA)
- Corresponding author
- Xu, Huaxi
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 87
- Issue
- 5
- Pages
- 963-975
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4575284
- OpenAlex
- W1918417411
- Cited by
- 98
- References
- 53
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 5 · 2021: 15 · 2020: 7 · 2019: 12 · 2018: 14 · 2017: 11 · 2016: 11
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Update notices
- erratum (2024-12-04)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Alzheimer's Association
- Wellcome Trust (089703, 081864)
- National Natural Science Foundation of China (91332114, U1405222, 91332112, 81161120496, 81225008)
- University of Toronto
- National Institutes of Health (1pn1ey016525-01)
- Medical Research Council (MC_G1000734)
- National Institute on Aging (R01AG044420, R01AG038710, R01AG027924, R01AG018440, P50AG005131, R01AG011385, R01AG5131, R01AG021173, RF1AG046205, R01AG035355, P50AG016574)
- National Eye Institute ((PN1 EY016525, PN2EY016525)
- National Institute of Neurological Disorders and Stroke (P30NS076411, R01NS076411, R01NS066072, R01NS046673, P01NS074969)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- caspase-3, tau cleavage, progressive supranuclear palsy, tau aggregation, synaptic dysfunction, T allele, tau transgenic mice, Alzheimer's disease, frontotemporal dementia, motor impairment, apoptosis
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Myelin Proteins, Supranuclear Palsy, Progressive, tau Proteins, Apoptosis, Hand Strength, Polymorphism, Single Nucleotide, Apoptosis Regulatory Proteins, Mice, Rats, Caspase 3
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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