ABSTRACT
Dietary influences on Alzheimer disease (AD) are gaining recognition. Because many aging processes are attenuated in laboratory mammals by caloric restriction (CR), we examined the effects of short-term CR in two AD-transgenic mice, APP(swe/ind) (J20) and APP(swe) + PS1(M146L) (APP + PS1). CR substantially decreased the accumulation of Abeta-plaques in both lines: by 40% in APP(swe/ind) (CR, 6 weeks), and by 55% in APP + PS1 (CR, 14 weeks). CR also decreased astrocytic activation (GFAP immunoreactivity). These influences of CR on AD-transgenic mice are consistent with epidemiological reports that show that high caloric diets associate with the risk of AD, and suggest that dietary interventions in adult life might slow disease progression.
Subject(s)
Alzheimer Disease/diet therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Caloric Restriction/methods , Plaque, Amyloid/metabolism , Alzheimer Disease/genetics , Amyloid beta-Peptides/genetics , Animals , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Brain/metabolism , Brain/pathology , Disease Models, Animal , Glial Fibrillary Acidic Protein/metabolism , Humans , Immunohistochemistry/methods , Membrane Proteins/genetics , Mice , Mice, Transgenic , Neurofibrillary Tangles/metabolism , Presenilin-1 , RNA, Messenger/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction/methodsABSTRACT
Inflammation has been argued to play a primary role in the pathogenesis of Alzheimer's disease (AD). Lipopolysaccharide (LPS) activates the innate immune system, triggering gliosis and inflammation when injected in the central nervous system. In studies described here, APP transgenic mice were injected intrahippocampally with 4 or 10 microg of LPS and evaluated 1, 3, 7, 14, or 28 days later. Abeta load was significantly reduced at 3, 7, and 14 days but surprisingly returned near baseline 28 days after the injection. No effects of LPS on congophilic amyloid deposits could be detected. LPS also activated both microglia and astrocytes in a time-dependent manner. The GFAP astrocyte reaction and the Fcgamma receptor microglial reaction peaked at 7 days after LPS injection, returning to baseline by 2 weeks postinjection. When stained for CD45, microglial activation was detected at all time points, although the morphology of these cells transitioned from an ameboid to a ramified and bushy appearance between 7 and 14 days postinjection. These results indicate that activation of brain glia can rapidly and transiently clear diffuse Abeta deposits but has no effect on compacted fibrillar amyloid.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Lipopolysaccharides/administration & dosage , Alzheimer Disease/pathology , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Astrocytes/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Routes , Hippocampus/drug effects , Hippocampus/pathology , Injections , Mice , Mice, Transgenic , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Time FactorsABSTRACT
Mice transgenic for mutated forms of the amyloid precursor protein (APP) plus presenilin-1 (PS1) genes (APP + PS1 mice) gradually develop memory deficits which correlate with the extent of amyloid deposition. The expression of several immediate-early genes (IEGs: Arc, Nur77 and Zif268) and several other plasticity-related genes (GluR1, CaMKIIalpha and Na-K- ATPase alphaIII) critical for learning and memory was normal in young APP + PS1 mice preceding amyloid deposition, but declined as mice grew older and amyloid deposits accumulated. Gene repression was less in APP + PS1 mouse brain regions that contain less Abeta and in APP mice compared with APP + PS1 mice, further linking the extent of amyloid deposition and the extent of gene repression. Critically, we demonstrated that amyloid deposition led specifically to impaired induction of the IEGs with no effects on basal expression using exposure to a novel environment 30 min prior to being killed to induce IEGs. These data imply that Abeta deposition can selectively reduce expression of multiple genes linked to synaptic plasticity, and provide a molecular basis for memory deficiencies found in transgenic APP mice and, most likely, in early stage Alzheimer's disease (AD). Presumably, pharmacological agents blocking the Abeta-related inhibition of gene expression will have benefit in AD.
