Physiological levels of β-amyloid increase tyrosine phosphorylation and cytosolic calcium

doi:10.1016/0006-8993(95)00282-U

Brain Research

Volume 681, Issues 1–2, 29 May 1995, Pages 65-74

https://doi.org/10.1016/0006-8993(95)00282-U Get rights and content

Abstract

The a β peptide is a neurotoxic peptide that accumulates in the brains of Alzheimer patients, but is also present in body fluids at subnanomolar levels. The potential effects of these low levels of a β are unclear. We now show that one such action is to increase tyrosine phosphorylation in PC12 cells and olfactory neuroblasts. Application of a β_25–35 or a β_1–40 induces a dose-dependent increase in the tyrosine phosphorylation in both whole cells and in vitro. The increase in tyrosine phosphorylation is both rapid and sensitive, being stimulated by picomolar doses of a β and occurring within 1 min of application. Calcium imaging experiments provide further support for the role of tyrosine phosphorylation in the action of a β. While a β does not alter calcium metabolism under basal conditions, the addition of a β induces a rapid increase in cytoplasmic calcium in olfactory neuroblasts that have been treated with the tyrosine phosphatase inhibitor, sodium orthovanadate or in PC12 cells treated with nerve growth factor. These responses could be blocked by the tyrosine kinase inhibitor, herbimycin. These calcium responses displayed an obligate requirement for the presence of matrix proteins. The identification of a rapid, sensitive assay for the action of a β may facilitate investigations of its mechanism of action.

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Therefore, the Aऔ-induced dysfunction of cortical and hippocampal neurons, not their death, may be largely responsible for the impairments in learning and memory associated with AD. Previous studies have found that Aऔ administration induced a marked increase in the tyrosine phosphorylation of multiple proteins in nerve cell lines and cortical cultures (49-51), suggesting that Aऔ has the potential to modulate cellular responses to growth factors and extracellular matrix molecules. In this study, we report a rapid and potent activation of two important serine/threonine kinases, PKC and CaMKII, in response to Aऔ25–35, Aऔ1–42, and Aऔ1–40 in cortical slices.
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View full text

Physiological levels of β-amyloid increase tyrosine phosphorylation and cytosolic calcium

Abstract

J. Biol. Chem.

Cell

Brain Res.

Neuron

Biol. Psych.

J. Biol. Chem.

Giant multilevel cation channels formed by Alzheimer disease β-protein [A β P-(1–40] in bilayer membranes

Alzheimer disease amyloid β protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum

Soluble β-amyloid induction of Alzheimer's phenotype for human fibroblast K+ channels

Science

Apoptosis mediated neurotoxicity induced by chronic application of β amyloid fragment 25–35

NeuroReport

A 109-amino-acid C-terminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion

Biochem. J.

Segregation of a missence mutation in the amyloid precursor protein gene with familial Alzheimer's disease

Nature

Secreted β-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation

Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor

Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation

Nature

Amyloid β-peptide is produced by cultured cells during normal metabolism

Nature

Soluble β-amyloid induction of Alzheimer's phenotype for human fibroblast K⁺ channels