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Updated: Nov 6, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study
Kaitlin B Casaletto1, Henrik Zetterberg2, Kaj Blennow2
1From the Memory and Aging Center (K.B.C., N.D., M.Y., S.W.-L., C.F., B.L.M., J.K.), Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco; Department of Psychiatry and Neurochemistry (H.Z., K.B., A.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z., K.B., A.B.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease (H.Z., K.B., A.B.), UCL Institute of Neurology, Queen ; UK Dementia Research Institute at UCL (H.Z.), London, UK; Department of Psychiatry (W.H.), University of British Columbia, Vancouver, Canada; and Department of Neurological Sciences (J.A.S., D.A.B.), Rush Medical College, Chicago, IL. kaitlin.casaletto@ucsf.edu.
Objective:
To test the hypothesis that fundamental relationships along the amyloid, tau, and neurodegeneration (A/T/N) cascade depend on synaptic integrity in older adults in vivo and postmortem.
Methods:
The 2 independent observational, cross-sectional cohorts included (1) in vivo community-dwelling, clinically normal adults from the University of California, San Francisco Memory and Aging Center who completed lumbar puncture and MRI (exclusion criteria, Clinical Dementia Rating score >0) and (2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In vivo measures included CSF synaptic proteins (synaptotagmin-1, synaptosome associated protein-25, neurogranin, and growth associated protein-43), β-amyloid (Aβ42/40), tau phosphorylated at amino acid 181 (ptau181), and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, vesicle associated membrane protein (VAMP), and SNARE complex) and neuritic plaque and neurofibrillary tangle (NFT) counts. Regression models tested statistical moderation of synaptic protein levels along the A/T/N cascade (synaptic proteins × amyloid on tau, and synaptic proteins × tau on GMV).
Results:
Sixty-eight in vivo older adults (age 71 years, 43% female) and 633 decedents (age 90 years, 68% female, 34% clinically normal) were included. Each in vivo CSF synaptic protein moderated the relationship between Aβ42/40 and ptau181 (-0.23 < β < -0.12, p < 0.05) and the relationship between ptau181 and GMV (-0.49 <β < -0.32, p < 0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau181 and ptau181-brain volume, effects that were absent or reversed in those with more normal CSF synaptic protein. Postmortem analyses recapitulated CSF models. More normal brain tissue levels of complexin-I, VAMP, and SNARE moderated the adverse relationship between neuritic plaque and NFT counts (-0.10 <β < -0.08, p < 0.05).
Conclusions:
Pathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk or resilience to AD proteinopathy.
