The cholinergic neuronal phenotype in Alzheimer's disease.
The synthesis, storage and release of acetylcholine (ACh) requires the expression of several specialized proteins, including choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). The VAChT gene is located within the first intron of the ChAT gene. This unique genomic organization permits coordinated activation of expression of the two genes by extracellular factors. Much less is known about factors that reduce the expression of the cholinergic phenotype. A cholinergic deficit is one of the primary features of Alzheimer's disease (AD), and AD brains are characterized by amyloid deposits composed primarily of A beta peptides. Although A beta peptides are neurotoxic, part of the cholinergic deficit in AD could be attributed to the suppression of cholinergic markers in the absence of cell death. Indeed, we and others demonstrated that synthetic A beta peptides, at submicromolar concentrations that cause no cytotoxicity, reduce the expression of cholinergic markers in neuronal cells. Another feature of AD is abnormal phospholipid turnover, which might be related to the progressive accumulation of apolipoprotein E (apoE) within amyloid plaques, leading perhaps to the reduction of apoE content in the CSF of AD patients. ApoE is a component of very low density lipoproteins (VLDL). As a first step in investigating a potential neuroprotective function of apoE, we determined the effects of VLDL on ACh content in neuronal cells. We found that VLDL increases ACh levels, and that it can partially offset the anticholinergic actions of A beta peptides.
Blusztajn
J K
JK
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, MA 02118, USA. jbluszta@bu.edu
Berse
B
B
D000109:Acetylcholine / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000235:genetics; D002874:Chromosome Mapping; D006801:Humans; D026901:Membrane Transport Proteins; D009474:Neurons / Q000502:physiology*; D010641:Phenotype; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine