PERK activation occurs predominantly in neurons with immature tau tangles across Braak stages in the human Alzheimer’s disease hippocampus

The endoplasmic reticulum unfolded protein response (UPR), particularly the PERK pathway, is activated in Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, it remains unclear whether PERK activation is sustained throughout tangle development or is restricted to a specific stage of tau pathology maturation. We used multiplex immunohistochemistry and single-cell image analysis to map pPERK activation in post-mortem hippocampal tissue from AD, PD, and neurologically normal cases, relative to a spectrum of tau maturity markers, α-synuclein, p62, and ubiquitin. pPERK predominantly labelled granulovacuolar degeneration bodies in CA1 and CA2/3 neurons. While the total number of pPERK+ neurons was elevated in AD, the proportion of tau+ cells expressing pPERK remained consistent across Braak stages. Individual cell profiling revealed that pPERK was restricted to neurons with early-stage tau tangle profiles (high AT8 and T231, low 3R and 4R) and was rarely present in neurons containing mature tangle markers (high 4R and 3R, low AT8 and T231) and protein degradation markers p62 and ubiquitin. In the PD hippocampus, pPERK was observed in neurons containing tau tangles but not α-synuclein aggregates. Our findings indicate that UPR activation via PERK is a feature of early-stage tau-mediated proteostatic stress. The absence of pPERK in neurons with mature tangles suggests that this response may be transient rather than cumulative. We propose that this may represent a therapeutic window during the initial phases of protein misfolding, when modulating the cellular response to early-stage protein misfolding may offer the greatest neuroprotective potential.