beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity

Abstract

In Alzheimer's disease (AD), abnormal accumulations of beta-amyloid are present in the brain and degenerating neurons exhibit cytoskeletal aberrations (neurofibrillary tangles). Roles for beta-amyloid in the neuronal degeneration of AD have been suggested based on recent data obtained in rodent studies demonstrating neurotoxic actions of beta-amyloid. However, the cellular mechanism of action of beta-amyloid is unknown, and there is no direct information concerning the biological activity of beta-amyloid in human neurons. We now report on experiments in human cerebral cortical cell cultures that tested the hypothesis that beta-amyloid can destabilize neuronal calcium regulation and render neurons more vulnerable to environmental stimuli that elevate intracellular calcium levels. Synthetic beta-amyloid peptides (beta APs) corresponding to amino acids 1-38 or 25-35 of the beta-amyloid protein enhanced glutamate neurotoxicity in cortical cultures, while a peptide with a scrambled sequence was without effect. beta APs alone had no effect on neuronal survival during a 4 d exposure period. beta APs enhanced both kainate and NMDA neurotoxicity, indicating that the effect was not specific for a particular subtype of glutamate receptor. The effects of beta APs on excitatory amino acid (EAA)-induced neuronal degeneration were concentration dependent and required prolonged (days) exposures. The beta APs also rendered neurons more vulnerable to calcium ionophore neurotoxicity, indicating that beta APs compromised the ability of the neurons to reduce intracellular calcium levels to normal limits. Direct measurements of intracellular calcium levels demonstrated that beta APs elevated rest levels of calcium and enhanced calcium responses to EAAs and calcium ionophore. The neurotoxicity caused by EAAs and potentiated by beta APs was dependent upon calcium influx since it did not occur in calcium-deficient culture medium. Finally, the beta APs made neurons more vulnerable to neurofibrillary tangle-like antigenic changes induced by EAAs or calcium ionophore (i.e., increased staining with tau and ubiquitin antibodies). Taken together, these data suggest that beta-amyloid destabilizes neuronal calcium homeostasis and thereby renders neurons more vulnerable to environmental insults.

Mechanisms of Cell Death Induced by the Mitochondrial Toxin 3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed Apoptosis

“…Recent findings indicate that a primary target of ␤-amyloid peptide is SDH (Kaneko et al, 1995) and that ␤-amyloid peptide results in the loss of energy homeostasis (Zhang et al, 1996). Moreover, ␤-amyloid can induce apoptotic neuronal death (Loo et al, 1993) and exacerbate glutamate toxicity (Koh et al, 1990;Mattson et al, 1992). The 3-NP model established in the current study is therefore relevant to acute insults such as ischemia, as well as neurodegenerative disorders, including Huntington's disease and Alzheimer's disease.…”

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

“…47 Briefly, meninges-free cortices were isolated, trypsinized and mechanically dissociated by passage through fire-polished Pasteur pipettes. Washed cells were plated (200 000 cells cm À2 ) onto poly-L-lysine (0.05 mg ml À1 ) and laminin (0.1 mg ml À1 )-coated tissue culture coverslips (Fisher Brand; Fisher Scientific, Pittsburgh, PA, USA) in NBM with L-glutamine, B-27 and P/S supplements (complete NBM).…”

Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-β levels in female rats

“…In the hippoca mpus amyloid protein precursor, a single pass transmembrane protein, is cleaved by secretases into Aβ40 and Aβ42. Increases in the secretion and aggregation of Aβ molecules are thought to be responsible for cell toxicity and memory impairment in AD (Koh et al, 1990;Yankner et al, 1990;Mattson et al, 1992Mattson et al, , 1993Morgan et al, 2000;Naslund et al, 2000). A series of studies have shown that levels of soluble Aβ correlate with the degree of cognitive impairment and disease progression in animal models and AD subjects (Kuo et al, 1996;McLean et al, 1999;Mucke et al, 2000;Naslund et al, 2000) whereas increasing evidence has suggested that soluble non-fibrillar Aβ rather than the insoluble fibrillar counterpart is important for the pathophysiology of the disease (Walsh 1999;Lambert et al, 2000).…”