Tripartite Relationship Among Synaptic, Amyloid, and Tau Proteins: An In Vivo and Postmortem Study.

Abstract

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:

Two independent observational, cross-sectional cohorts: 1) in-vivo community-dwelling, clinically normal adults from the UCSF Memory and Aging Center completed lumbar puncture and MRI (exclusion criteria, CDR>0), and 2) postmortem decedents from the Rush Memory and Aging Project (exclusion criteria, inability to sign informed consent). In-vivo measures included cerebrospinal fluid (CSF) synaptic proteins (synaptotagmin-1, SNAP-25, neurogranin, and GAP-43), Aβ42/40, ptau181, and MRI gray matter volume (GMV). Postmortem measures captured brain tissue levels of presynaptic proteins (complexin-I, complexin-II, 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:

68 in-vivo older adults (age=71y, 43%F) and 633 decedents (age=90y, 68%F, 34% clinically normal) were included. Each in-vivo CSF synaptic protein moderated the relationship between Aβ42/40 and ptau181 (-0.23<��s<-0.12, ps<0.05) and the relationship between ptau and GMV (-0.49<��s<-0.32, ps<0.05). Individuals with more abnormal CSF synaptic protein demonstrated expected relationships between Aβ-ptau and ptau-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<��s<-0.08, ps<0.05).

CONCLUSIONS:

Pathogenic relationships of Aβ and tau may depend on synaptic state. Synaptic markers may help identify risk and/or resilience to AD proteinopathy.

• Authors: Kaitlin Blackstone Casaletto, Henrik Zetterberg, Kaj Blennow, Ann Brinkmalm, William Honer, Julie A Schneider, David A Bennett, Nina Djukic, Michelle You, Sophia Weiner-Light, Corrina Fonseca, Bruce L Miller, Joel Kramer
• Journal: Neurology (Neurology) (May 04 2021) ISSN: 1526-632X [Electronic] United States
• PMID: 33947778 (Publication Type: Journal Article)
• Copyright: © 2021 American Academy of Neurology.