ABSTRACT
BACKGROUND: Most Alzheimer's disease (AD) cases arise sporadically and may involve innate immune activation of microglial expressed Toll-like receptors regulated through the myeloid differentiation protein 88 (MyD88) pathway. OBJECTIVE: It was the aim of this study to test the innate immune involvement in AD pathology. METHODS: We mated APPsw/PS1ΔE9 mice with MyD88-deficient mice. RESULTS: Progeny mice had similar levels of soluble amyloid-ß peptides, amyloid plaque density and neuroimmune staining patterns. However, double-transgenic mice did show a significantly reduced life expectancy. CONCLUSION: Our findings indicate that impaired innate immune responses may play a role in AD pathology.
Subject(s)
Alzheimer Disease/immunology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Brain/pathology , Myeloid Differentiation Factor 88/deficiency , Amyloid beta-Peptides/metabolism , Animals , Brain/immunology , Brain/metabolism , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Fluorescent Antibody Technique , Mice , Mice, Transgenic , Plaque, Amyloid/pathology , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Nicotine dependence (ND) is one of the world's leading causes of preventable death. Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the world. Evidence for a genetic influence on smoking behaviour and ND has prompted a search for susceptibility genes. Evidence has recently accumulated that single nucleotide polymorphisms (SNPs) in the genetic region encoding the nicotinic acetylcholine receptor (nAChR) subunits α6, α5, α3, and ß4 are associated with smoking and ND. Brain nAChR are a heterogeneous family of ion channels expressed in the various parts of the brain. A number of studies suggest that brain nAChR are critical targets for the development of pharmacotherapy for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Additionally, we will provide an overview of the three major pharmacotherapies for smoking cessation (which have demonstrated efficacy) such as: nicotine replacement therapy (NRT), bupropion, and varenicline. An appreciation of the complexity of nAChR and their regulation will be necessary for the development of nAChR modulators as potential pharmacotherapy for drug addiction. Prevention strategies should be tailored to carriers of SNPs located on chromosome 15q and that are strongly associated with nicotine dependence and risk of lung cancer.