J Biol Chem, Vol. 273, Issue 20, 12548-12554, May 15, 1998

Amyloid Protein Precursor Stimulates Excitatory Amino Acid Transport
IMPLICATIONS FOR ROLES IN NEUROPROTECTION AND PATHOGENESIS

Eliezer Masliah, Jacob Raber^¶, Michael Alford, Margaret Mallory, Mark P. Mattson, Daseng Yang^¶, Derek Wong^¶, and Lennart Mucke^¶**

From the  Departments of Neurosciences and Pathology, University of California San Diego, La Jolla, California 92093-0624, the ^¶ Gladstone Institute of Neurological Disease and Department of Neurology, University of California San Francisco, San Francisco, California 94141-9100 the  Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536 and ^** Neuroscience Program, University of California, San Francisco, California 94141-9100

Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the amyloid protein precursor may participate in the regulation of this important process. The amyloid protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human amyloid protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by amyloid protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission.