• Pol Andrés-Benito, Margarita Carmona, Mónica Jordán Pirla, Benjamín Torrejón-Escribano, José Antonio Del Rio, and Isidro Ferrer.
• Department of Pathology and Experimental Therapeutics, University of Barcelona, CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, Bellvitge University Hospital/Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain. Electronic address: pandres@idibell.cat.
• Neuroscience. 2023 May 10; 518: 119140119-140.

AbstractThe hippocampus of cases with neurofibrillary tangles (NFT) pathology classified as stages I-II, III-IV, and V-VI without comorbidities, and middle-aged (MA) individuals with no NFT pathology, were examined to learn about the composition of granulovacuolar degeneration (GVD). Our results confirm the presence of CK1-δ, p38-P Thr180/Tyr182, SAPK/JNK-P Thr183/Thr185, GSK-3α/β-P Tyr279/Tyr216, and GSK-3β Ser9 in the cytoplasmic granules in a subset of neurons of the CA1 and CA2 subfields of the hippocampus. Also, we identify the presence of PKA α/β-P Thr197, SRC-P Tyr416, PAK1-P Ser199/Ser204, CAMK2A-P Tyr197, and PKCG-P Thr655 in cytoplasmic granules in cases with NFT pathology, but not in MA cases. Our results also confirm the presence of β-catenin-P Ser45/Thr41, IREα-P Ser274, eIF2α-P Ser51, TDP-43-P Ser403-404 (but absent TDP-43), and ubiquitin in cytoplasmic granules. Other components of the cytoplasmic granules are MAP2-P Thr1620/1623, MAP1B-P Thr1265, ADD1-P Ser726, and ADD1/ADD1-P Ser726/Ser713, in addition to several tau species including 3Rtau, 4Rtau, and tau-P Ser262. The analysis of GVD at progressive stages of NFT pathology reveals the early appearance of phosphorylated kinases and proteins in cytoplasmic granules at stages I-II, before the appearance of pre-tangles and NFTs. Most of these granules are not surrounded by LAMP1-positive membranes. Markers of impaired ubiquitin-protesome system, abnormal reticulum stress response, and altered endocytic and autophagic pathways occur in a subpopulation of neurons containing cytoplasmic granules, and they appear later. These observations suggest early phosphorylation of kinases leading to their activation, and resulting in the abnormal phosphorylation of various substrates, including tau, as a main alteration at the first stages of GVD.Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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