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, Lennart Mucke

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12548-12554
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number20
DOIs
StatePublished - May 15 1998
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Amyloid protein precursor stimulates excitatory amino acid transport. Implications for roles in neuroprotection and pathogenesis'. Together they form a unique fingerprint.

  • Cite this