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Cited by 25Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Amyloid-β oligomers increase the binding and internalization of tau oligomers in human synapses

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Kadamangudi, Shrinath, Marcatti, Michela, Zhang, Wen-Ru, Fracassi, Anna, Kayed, Rakez, Limon, Agenor, Taglialatela, Giulio·2024·Acta Neuropathologica
DOI 10.1007/s00401-024-02839-2PMC PMC11652575
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Abstract

In Alzheimer's disease (AD), the propagation and spreading of CNS tau pathology closely correlates with cognitive decline, positioning tau as an attractive therapeutic target. Amyloid beta (Aβ) has been strongly implicated in driving tau spread, whereas primary tauopathies such as primary age-related tauopathy (PART)-which lack Aβ pathology-exhibit limited tau spread and minimal-to-no cognitive decline. Emerging evidence converges on a trans-synaptic mechanism of tau spread, facilitated by the transfer of misfolded tau aggregates (e.g. soluble oligomers). However, it is unclear whether Aβ oligomers modulate the binding and internalization of tau oligomers in human synapses. Our translationally focused paradigms utilize post-mortem brain specimens from Control, PART, and AD patients. Synaptosomes isolated from the temporal cortex of all three groups were incubated with preformed recombinant tauO (rtauO), ± preformed recombinant AβO (rAβO), and oligomer binding/internalization was quantified via flow cytometry following proteinase K (PK) digestion of surface-bound oligomers. TauO-synapse interactions were visualized using EM immunogold. Brain-derived tau oligomers (BDTO) from AD and PART PBS-soluble hippocampal fractions were co-immunoprecipitated and analyzed via mass spectrometry to compare synaptic tauO interactomes in primary and secondary tauopathies, thereby inferring the role of Aβ. AD synaptosomes, enriched in endogenous Aβ pathology, exhibited increased rtauO internalization compared to PART synaptosomes. This observation was mirrored in Control synaptosomes, where recombinant rAβO significantly increased rtauO binding and internalization. PK pre-treatment abolished this effect, implicating synaptic membrane proteins in AβO-mediated tauO internalization. While both PART and AD BDTO were broadly enriched in synaptic proteins, AD BDTO exhibited differential enrichment of endocytic proteins across pre- and post-synaptic compartments, whereas PART BDTO showed no significant synaptic enrichment. This study demonstrates that Aβ oligomers enhance tau oligomer binding and drive its internalization through synaptic membrane proteins. These findings offer novel mechanistic insights underlying pathological tau spreading directly within human synapses and emphasize the therapeutic potential of targeting Aβ-tau interactions.

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Authors
Kadamangudi, S., Marcatti, M., Zhang, W.-R., Fracassi, A., Kayed, R., Limon, A., & Taglialatela, G.
Affiliations
The University of Texas Medical Branch at Galveston (US)
Corresponding author
Taglialatela, Giulio
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2024-12-17
Volume
149
Issue
1
Pages
2-2
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-024-02839-2
PMC
PMC11652575
OpenAlex
W4405461250
Cited by
25
References
160
Citations by year
2026: 16 · 2025: 9
FWCI
7.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (F30AG085974, R01AG072883)
  • University of Texas Medical Branch (Kempner Fellowship)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta oligomers, tau oligomers, Alzheimer's disease, primary age-related tauopathy, tau propagation, trans-synaptic spread, synapses, synaptic membrane proteins, endocytosis, synaptosomes, postmortem brain
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Middle Aged, Protein Binding, Synapses, Synaptosomes, Amyloid beta-Peptides, tau Proteins, Tauopathies

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