title: Transgenic AD model mice, effects of potential anti-AD treatments on inflammation and pathology.
abstract: The extracellular deposition of amyloid (A) peptides in plaques, and neurofibrillary tangles are the two characteristic pathological features of Alzheimer's disease (AD). Plaques are surrounded by activated astrocytes and microglia, to study the relation between amyloid neuropathology and inflammation, we examined the changes in amyloid pathology in the hippocampus following three different treatments aimed at reducing the amyloid burden. (1) To investigate the effects of long-term cholinergic deafferentation, we lesioned the fimbria-fornix pathway in our AD-model mice at 7 months of age, and 11 months post-lesion the mice were sacrificed for histopathological analysis. The fimbria-fornix transection resulted in a substantial depletion of cholinergic markers in the hippocampus, but the lesion did not result in an alteration in hippocampal A deposition and inflammation (i.e., numbers or staining density of astrocytes and microglia). (2) To investigate the effects of estrogen, we ovariectomized mice and treated them with estrogen (sham-lesion, zero dose, low dose, and high dose) and studied the pathology at different postsurgery intervals. Estrogen depletion (i.e., ovariectomy) or estrogen replacement did not affect A deposition or inflammation at any time point. (3) In the final studies, we treated mice with flurbiprofen and an NO-donating derivative of flurbiprofen (HCT 1026) for several months (from 6 till 14 months of age), and studied the A pathology and inflammation in the brain. Sham treatment, flurbiprofen, and the low-dose HCT 1026 did not affect pathology; however, a higher dose of HCT 1026 reduced both A load and amount of microglial activation surrounding plaques.
authors.affiliation: Department of Neuroscience and Neurology, University of Kuopio, Canthia Building, Finland. thomas.vangroen@uku.fi
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D002091:Butyrylcholinesterase / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004967:Estrogens / Q000627:therapeutic use; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020712:Fornix, Brain / Q000293:injuries / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006651:Histocytochemistry / Q000379:methods; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000235:genetics; D010052:Ovariectomy / Q000379:methods; D011897:Random Allocation; D050494:Vesicular Acetylcholine Transport Proteins
chemical_list: D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D014150:Antipsychotic Agents; D039481:CD11b Antigen; D004967:Estrogens; D005904:Glial Fibrillary Acidic Protein; D026901:Membrane Transport Proteins; D009842:Oligopeptides; C449186:PS1 antigen; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase