The β-Amyloid Precursor Protein of Alzheimer’s Disease Enhances Neuron Viability and Modulates Neuronal Polarity

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Abstract
β-Amyloid precursor protein (βPP) can reside at neuron and glial cell surfaces or undergo proteolytic processing into secreted fragments. Although βPP has been studied extensively, its precise physiological role is unknown. A line of transgenic knock-out mice selectively deficient in βPP survive and breed but exhibit motor dysfunction and brain gliosis, consistent with a physiological role for βPP in neuron development. To elucidate these functions, we cultured hippocampal neurons from wild-type and βPP-deficient mice and compared their ability to attach, survive, and develop neurites. We found that hippocampal neurons from βPP-deficient mice had diminished viability and retarded neurite development. We also compared the effects of βPP secretory products, released from wild-type astrocytes, on process outgrowth from wild-type and βPP-deficient hippocampal neurons. Outgrowth was enhanced at 1 d in the presence of wild-type astrocytes, as compared with βPP-deficient astrocytes. However, by 3 d, neurons had shorter axons but more minor processes with more branching when cocultured with wild-type astrocytes, as compared with βPP-deficient astrocytes. Our data demonstrate that cell-associated neuronal βPP contributes to neuron viability, axonogenesis, and arborization and that βPP secretory products modulate axon growth, dendrite branching, and dendrite numbers.