Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice

Epidemiological studies have established that the epsilon 4 allele of the A poE gene (ApoE4) constitutes an important risk factor for Alzheimer's disea se and might influence the outcome of central nervous system injury. The me chanism by which ApoE4 contributes to the development of neurodegeneration remains unknown. To test one hypothesis or mode of action of ApoE, we gener ated transgenic mice that overexpressed human ApoE4 in different cell types in the brain, using four distinct gene promoter constructs. Many transgeni c mice expressing ApoE4 in neurons developed motor problems accompanied by muscle wasting, loss of body weight, and premature death Overexpression of human ApoE4 in neurons resulted in hyperphosphorylation of the microtubule- associated protein tau. In three independent transgenic lines from two diff erent promoter constructs, increased phosphorylation of protein tau was cor related with ApoE4 expression levels. Hyperphosphorylation of protein tau i ncreased with age. In the hippocampus, astrogliosis and ubiquitin-positive inclusions were demonstrated. These findings demonstrate that expression of ApoE in neurons results in hyperphosphorylation of protein tau and suggest s a role for ApoE in neuronal cytoskeletal stability and metabolism.