PMID- 28865749 OWN - NLM STAT- MEDLINE DCOM- 20180723 LR - 20180723 IS - 1095-953X (Electronic) IS - 0969-9961 (Linking) VI - 108 DP - 2017 Dec TI - Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease. PG - 307-323 LID - S0969-9961(17)30209-7 [pii] LID - 10.1016/j.nbd.2017.08.019 [doi] AB - Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Abeta) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Abeta pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Iulita, M Florencia AU - Iulita MF AD - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada. FAU - Bistue Millon, M Beatriz AU - Bistue Millon MB AD - Facultad de Ciencias Medicas, Universidad Catolica de Cuyo-CONICET, San Juan, Argentina. FAU - Pentz, Rowan AU - Pentz R AD - Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. FAU - Aguilar, Lisi Flores AU - Aguilar LF AD - Department of Anatomy and Cell Biology, McGill University, Montreal, Canada. FAU - Do Carmo, Sonia AU - Do Carmo S AD - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada. FAU - Allard, Simon AU - Allard S AD - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada. FAU - Michalski, Bernadeta AU - Michalski B AD - Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada. FAU - Wilson, Edward N AU - Wilson EN AD - Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. FAU - Ducatenzeiler, Adriana AU - Ducatenzeiler A AD - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada. FAU - Bruno, Martin A AU - Bruno MA AD - Facultad de Ciencias Medicas, Universidad Catolica de Cuyo-CONICET, San Juan, Argentina. FAU - Fahnestock, Margaret AU - Fahnestock M AD - Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada. FAU - Cuello, A Claudio AU - Cuello AC AD - Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Canada. Electronic address: claudio.cuello@mcgill.ca. LA - eng PT - Journal Article DEP - 20170901 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (APP protein, human) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (RNA, Messenger) RN - 9061-61-4 (Nerve Growth Factor) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, rat) SB - IM MH - Aging/metabolism/pathology MH - Alzheimer Disease/*metabolism/pathology MH - Amyloid beta-Protein Precursor/genetics/metabolism MH - Animals MH - Blotting, Western MH - Brain/*metabolism/pathology MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Disease Models, Animal MH - Disease Progression MH - Female MH - Gene Expression Regulation MH - Humans MH - Immunohistochemistry MH - Male MH - Matrix Metalloproteinase 9/metabolism MH - Nerve Growth Factor/*metabolism MH - Neurons/metabolism/pathology MH - Plaque, Amyloid/metabolism/pathology MH - RNA, Messenger/metabolism MH - Rats, Transgenic OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid-beta OT - BDNF OT - Cholinergic OT - MMP-9 OT - Nerve growth factor OT - Neuroserpin OT - Neurotrophins OT - Synaptic plasticity OT - proNGF OT - tPA EDAT- 2017/09/04 06:00 MHDA- 2018/07/24 06:00 CRDT- 2017/09/04 06:00 PHST- 2017/02/22 00:00 [received] PHST- 2017/08/08 00:00 [revised] PHST- 2017/08/29 00:00 [accepted] PHST- 2017/09/04 06:00 [pubmed] PHST- 2018/07/24 06:00 [medline] PHST- 2017/09/04 06:00 [entrez] AID - S0969-9961(17)30209-7 [pii] AID - 10.1016/j.nbd.2017.08.019 [doi] PST - ppublish SO - Neurobiol Dis. 2017 Dec;108:307-323. doi: 10.1016/j.nbd.2017.08.019. Epub 2017 Sep 1.