Hypocapnia induces caspase-3 activation and increases Abeta production.
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.


METHODS
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.


CONCLUSIONS
The findings suggest that hypocapnia (e.g. during general anesthesia) could exacerbate AD neuropathogenesis.
Xie
Zhongcong
Z
Genetics and Aging Research Unit, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129-4404, USA.
Moir
Robert D
RD
Romano
Donna M
DM
Tesco
Giuseppina
G
Kovacs
Dora M
DM
Tanzi
Rudolph E
RE
D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016857:Hypocapnia / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D053764:Presenilin-1; D014162:Transfection
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases