title: Deafferentation of the septo-hippocampal pathway in rats as a model of the metabolic events in Alzheimer's disease.
abstract: Changes in the metabolic activity within the brain of patients suffering from Alzheimer's disease (AD) were investigated and compared with biochemical alterations in the hippocampus induced by fimbria/fornix transection in the rat. The deafferentation of the hippocampus results in a degeneration of cholinergic septo-hippocampal terminals accompanied by a persistent decrease of choline acetyltransferase (ChAT) and acetylcholine esterase (AChE) activities similar to the cholinergic malfunction in AD. In the animal model the [3H]-cytochalasin B binding to the glucose transporters was elevated up to the day 7 after surgery as was the activity of the phosphofructokinase (PFK) on day 3. A reactive astrogliosis could be evidenced by the upregulation of glial fibrillary acidic protein (GFAP). An increase of the PFK activity was also found in AD being accompanied by enhanced level of GFAP as well. A higher concentration of mRNA for all three isoenzymes of PFK was shown by reverse transcription (RT)-real time polymerase chain reaction (PCR) amplification. However, the pattern of PFK isoenzyme proteins and mRNAs did neither change in diseased human nor in the lesioned rat brain. The activities of the mitochondrial enzymes pyruvate dehydrogenase complex (PDHC) and cytochrome c oxidase (CO) were diminished in the lesioned rat hippocampus on day 7 as well as in AD brain. Subcellular fractionation showed that the activity of these enzymes was affected in the synaptosomal as well as in the extrasynaptosomal mitochondria indicating a loss of neuronal input and also a vulnerability of intrinsic hippocampal neurons and/or non-neuronal cells. The recovery of the mitochondrial enzyme activity in the animal model at later post lesion intervals may be the result of compensatory responses of surviving cells or of sprouting of other non-affected inputs. It is concluded that common metabolic mechanisms may underlie the concurrent degenerative and repair processes in the denervated hippocampus and the diseased Alzheimer brain.
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Härtelstrasse 16-18, D-04107, Leipzig, Germany. krueu@medizin.uni-leipzig.de
authors.forename: U
authors.initials: U
authors.lastname: Krügel
authors.forename: V
authors.initials: V
authors.lastname: Bigl
authors.forename: K
authors.initials: K
authors.lastname: Eschrich
authors.forename: M
authors.initials: M
authors.lastname: Bigl
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000344:Afferent Pathways; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000737:chemistry / Q000378:metabolism; D020532:Basal Nucleus of Meynert / Q000166:cytology* / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000378:metabolism; D003714:Denervation; D020667:Diagonal Band of Broca / Q000166:cytology* / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D020712:Fornix, Brain / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D015971:Gene Expression Regulation, Enzymologic; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D010732:Phosphofructokinase-1 / Q000235:genetics / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005904:Glial Fibrillary Acidic Protein; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D003576:Electron Transport Complex IV; D002795:Choline O-Acetyltransferase; D010732:Phosphofructokinase-1; D000110:Acetylcholinesterase