The cholinergic neuronal phenotype in Alzheimer's disease

The synthesis, storage and release of acetylcholine (ACh) requires the expr ession 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 extracell ular factors. Much less is known about factors that reduce the expression o f the cholinergic phenotype. A cholinergic deficit is one of the primary fe atures of Alzheimer's disease (AD), and AD brains are characterized by amyl oid deposits composed primarily of A beta peptides. Although A beta peptide s are neurotoxic, part of the cholinergic deficit in AD could be attributed to the suppression of cholinergic markers in the absence of cell death. In deed, we and others demonstrated that synthetic A beta peptides, at submicr omolar concentrations that cause no cytotoxicity, reduce the expression of cholinergic markers in neuronal cells. Another feature of AD is abnormal ph ospholipid 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 p otential neuroprotective function of apoE, we determined the effects of VLD L on ACh content in neuronal cells. We found that MDL increases ACh levels, and that it can partially offset the anticholinergic actions of A beta pep tides.