Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain - PubMed (original) (raw)

Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain

K Furukawa et al. J Neurochem. 1996 Nov.

Erratum in

J Neurochem 1997 Mar;68(3):1331

Abstract

Proteolytic cleavage of beta-amyloid precursor protein (beta APP) by alpha-secretase results in release of one secreted form (sAPP) of APP (sAPP alpha), whereas cleavage by beta-secretase releases a C-terminally truncated sAPP (sAPP beta) plus amyloid beta-peptide (A beta). beta APP mutations linked to some inherited forms of Alzheimer's disease may alter its processing such that levels of sAPP alpha are reduced and levels of sAPP beta increased. sAPP alpha s may play important roles in neuronal plasticity and survival, whereas A beta can be neurotoxic. sAPP alpha was approximately 100-fold more potent than sAPP beta in protecting hippocampal neurons against excitotoxicity, A beta toxicity, and glucose deprivation. Whole-cell patch clamp and calcium imaging analyses showed that sAPP beta was less effective than sAPP alpha in suppressing synaptic activity, activating K+ channels, and attenuating calcium responses to glutamate. Using various truncated sAPP alpha and sAPP beta APP695 products generated by eukaryotic and prokaryotic expression systems, and synthetic sAPP peptides, the activity of sAPP alpha was localized to amino acids 591-612 at the C-terminus. Heparinases greatly reduced the actions of sAPP alpha s, indicating a role for a heparin-binding domain at the C-terminus of sAPP alpha in receptor activation. These findings indicate that alternative processing of beta APP has profound effects on the bioactivity of the resultant sAPP products and suggest that reduced levels of sAPP alpha could contribute to neuronal degeneration in Alzheimer's disease.

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Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain - PubMed (original) (raw)