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Basic Science and Pathogenesis.

Guo Luo1, Jing Zhang1, Emmanuel Mignot1

  • 1Stanford University School of Medicine, Palo Alto, CA, USA.

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Summary
This summary is machine-generated.

An adaptive immune response targeting acetylated tau protein, specifically PHF6 aK311, mediated by HLA-DRB1*04:04, was found to decrease Alzheimer's disease (AD) risk. This suggests new therapeutic strategies for AD.

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Area of Science:

  • Immunology
  • Neuroscience
  • Genetics

Background:

  • Alzheimer's disease (AD) is characterized by neurofibrillary tangles (NFTs) formed by aggregated tau protein.
  • Tau acetylation, particularly the PHF6 region (VQIVYK), is crucial for tau aggregation.
  • The role of the adaptive immune system, including T cells and HLA types, in AD pathogenesis is not fully understood.

Purpose of the Study:

  • To investigate HLA associations with AD and Parkinson's disease (PD).
  • To explore the adaptive immune response to modified tau protein in AD.
  • To identify potential therapeutic targets for AD based on immune responses.

Main Methods:

  • Analyzed HLA associations in a large cohort (∼176,000) of individuals with AD/PD versus controls.
  • Compared postmortem brain NFT/amyloid plaque density and cerebrospinal fluid (CSF) tau/Aβ42 levels in AD patients and controls (∼8,000).
  • Conducted HLA binding, T cell tetramer studies, and T cell receptor (TCR) activation assays using tau PHF6 in Jurkat cells.

Main Results:

  • Identified HLA-DRB1*04:04 as having a protective effect against AD.
  • Detected T cells recognizing acetylated tau PHF6 (PHF6 aK311) presented by HLA-DRB1*04:04, with distinct phenotypes in AD patients versus controls.
  • Identified specific TCR clones activated by tau PHF6 aK311 presented by HLA-DRB1*04:04 in both AD patients and healthy controls.

Conclusions:

  • An HLA-DRB1*04-mediated adaptive immune response against tau PHF6 aK311 is associated with decreased AD risk.
  • This finding opens possibilities for novel therapeutic strategies targeting the immune system in AD.
  • Understanding specific T cell responses to modified tau may lead to new diagnostic and therapeutic approaches for AD.