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Neurodegener Dis. 2004;1(1):29-37.

Hypocapnia induces caspase-3 activation and increases Abeta production.

Author information

1
Genetics and Aging Research Unit, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129-4404, USA.

Abstract

BACKGROUND:

At least half of all cases of early onset (<60) familial Alzheimer's disease (FAD) are caused by any of over 150 mutations in three genes: the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). Mutant forms of PS1 have been shown to sensitize cells to apoptotic cell death.

OBJECTIVE:

We investigated the effects of hypocapnia, a risk factor for both cognitive and neurodevelopment deficits, on caspase-3 activation, apoptosis, and amyloid beta-protein (Abeta) production, and assessed the influence of the PS1Delta9 FAD mutation on these effects.

METHOD:

For this purpose, we exposed stably transfected H4 human neuroglioma cells to conditions consistent with hypocapnia (PCO2<40 mm Hg) and hypocapnia plus hypoxia (PO2<21%).

RESULTS:

Hypocapnia (20 mm Hg CO2 for 6 h) induced caspase-3 activation and apoptosis; the PS1Delta9 FAD mutation significantly potentiated these effects. Moreover, the combination of hypocapnia (20 mm Hg CO2) and hypoxia (5%O2) induced caspase-3 activation and apoptosis in a synergistic manner. Hypocapnia (5 and 20 mm Hg CO2 for 6 h) also led to an increased Abeta production.

CONCLUSION:

The findings suggest that hypocapnia (e.g. during general anesthesia) could exacerbate AD neuropathogenesis.

PMID:
16908971
DOI:
10.1159/000076667
[Indexed for MEDLINE]
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