Fig. 4.

Immune clearance of Acetylated PHF6 tau sequences may reduce neurodegeneration in AD and PD. Pathological tau seeds, soluble tau fragments, or misfolded tau present in the extracellular space are taken up and phagocytosed by activated microglia where it is processed. In addition to autophagy, resulting tau peptide fragments, notably acetylated lysine (K-ac) 311 PHF6 are bound to HLA-DRB1*04:01 or HLA-DRB1*04:04 and the resulting HLA-peptide complexes presented by microglial cells (or other antigen presenting cells) to CD4⁺ T helper cells. CD4⁺ T cells trigger beneficial downstream immune responses perhaps involving CD8⁺ T and antibody producing B cells. These responses limit propagation of misfolded tau and reduce neuropathology, also explaining reduced CSF tau in HLA-DRB1*04 individuals.