AMYLOID PROTEIN-PRECURSOR STIMULATES EXCITATORY AMINO-ACID-TRANSPORT - IMPLICATIONS FOR ROLES IN NEUROPROTECTION AND PATHOGENESIS

Excitatory neurotransmitters such as glutamate are required for the no rmal functioning of the central nervous system but can trigger excitot oxic neuronal injury if allowed to accumulate to abnormally high level s. 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 evoluti on, and a number of studies indicate that it may function as an endoge nous excitoprotectant. However, the mechanisms underlying this neuropr otective capacity remain largely unknown. At moderate levels of expres sion, human amyloid protein precursors increased glutamate/aspartate u ptake in brains of transgenic mice, with the 751-amino acid isoform sh owing greater potency than the 695-amino acid isoform. Cerebral glutam ate/aspartate transporter protein levels were higher in transgenic mic e than in non-transgenic controls, whereas transporter mRNA levels wer e unchanged. Amyloid protein precursor-dependent stimulation of aspart ate uptake by cultured primary astrocytes was associated with increase s in protein kinase A and C activity and could be blocked by inhibitor s of these kinases. The stimulation of astroglial excitatory amino aci d transport by amyloid protein precursors could protect the brain agai nst excitotoxicity and may play an important role in neurotransmission .