Basic Science and Pathogenesis

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.