The presence of the APP(swe) mutation in mice does not increase the vulnerability of cholinergic basal forebrain neurons to neuroinflammation.
Neuroinflammation, and elevated levels of inflammatory proteins, such as tumor necrosis factor-alpha, and the deposition of beta-amyloid may interact to contribute to the pathogenesis of Alzheimer's disease. We reproduced a component of the neuroinflammatory state within the basal forebrain cholinergic system, a region that is vulnerable to degeneration in Alzheimer's disease, of transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein (APPswe). We have previously shown that basal forebrain cholinergic neurons are selectively vulnerable to the consequences of neuroinflammation. In the current study, tumor necrosis factor-alpha was infused into the basal forebrain region of APPswe and nontransgenic control mice for 20 days with the expectation that the presence of the transgene would enhance the loss of cholinergic neurons. Chronic infusion of tumor necrosis factor-alpha significantly decreased cortical choline acetyltransferase activity, reduced the number of choline acetyltransferase-immunoreactive cells and increased the number of activated astrocytes and microglia within the basal forebrain. The presence of the APPswe gene did not enhance the vulnerability of forebrain cholinergic neurons to the chronic neuroinflammation. Furthermore, combined treatment of these mice with memantine demonstrated that the neurotoxic effects of tumor necrosis factor-alpha upon cholinergic cells did not require the activation of the N-methyl-d-aspartate receptors. In contrast, we have previously shown that memantine was able to provide neuroprotection to cholinergic forebrain neurons from the consequences of exposure to the inflammogen lipopolysaccharide. These results provide insight into the mechanism by which neuroinflammation may selectively target specific neural systems during the progression of Alzheimer's disease.
Wenk
G L
GL
Division of Neural Systems, Memory and Aging, University of Arizona, 350 Life Sciences North Building, Tucson, AZ 85724, USA. gary@nsma.arizona.edu
McGann-Gramling
K
K
Hauss-Wegrzyniak
B
B
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism; D002799:Cholinergic Fibers / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005911:Gliosis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
D016564:Amyloid beta-Protein Precursor; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine; D008559:Memantine