Fig. 3.

PNNs are reduced in the human AD cortex and correlate negatively with dense-core plaque load. (A-B) Representative stitched and 20X images of gray matter (GM) aggrecan (ACAN)+ PNNs immunolabeled in postmortem cortical tissue from the middle frontal gyrus (BA9 and BA46) of non-demented control or (C-D) clinically diagnosed AD patients reveals substantial PNN loss in the diseased brain, where Thio-S+ dense-core plaques (arrows) and immediately proximal IBA1+ PAMs accumulate. (E) Quantification of ACAN+ PNN number in sections from n = 9 non-demented control and n = 12 AD brains revealed a significant loss with disease (p<0.01; two-tailed unpaired t-test; n = 9–12/group) in parallel with (F) a significant increase in Thio-S+ dense core plaques in AD compared to non-demented control brains (p<0.001; two-tailed unpaired t-test; n = 9–12/group). (G) Nonlinear regression and correlational analysis of human PNN and dense-core plaque counts across all sample replicates from AD and non-demented control brains identified a nonlinear (Y = 13.91+−5.414*X + 0.7059*X²; r²=0.2094) and highly significant inverse relationship between PNNs and plaque count in human prefrontal cortex GM (Spearman's r=−0.49, p<0.0001; n = 80). (H-I) Representative 63X images of AD patient cortical GM displays colocalization of ACAN+ signal (clone 7D4) within Thio-S+ plaques and IBA1+ microglia, suggesting the presence of PNN material. As in 5xFAD mice, PAM processes were seen in contact with proximal PNNs, occasionally with morphology resembling phagocytic cups (arrow). Statistical significance is denoted by * p ≤ 0.05, ** p<0.01, *** p<0.001, **** p<0.0001, ns = not significant. Error bars indicate SEM.