Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection.

  • Chen G
  • Xu J
  • Lahousse S
 et al. 
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Familial Alzheimer's Disease (AD) has been linked to amyloid beta protein precursor (AbetaPP) and presenilin gene mutations. In sporadic AD, which accounts for the vast majority of cases, the pathogenesis of neurodegeneration is unknown; however, recent evidence suggests a role for oxidative stress. The present study demonstrates that transient hypoxic injury to cortical neurons causes several of the molecular and biochemical abnormalities that occur in AD including, mitochondrial dysfunction, impaired membrane integrity, increased levels of DNA damage, reactive oxygen species, phospho-tau, phospho-MAP-1B, and ubiquitin immunoreactivity, and AbetaPP cleavage with accumulation of Abeta-immunoreactive products. These abnormalities were associated with activation of kinases that phosphorylate tau, including glycogen synthase kinase 3beta (GSK-3beta), mitogen-activated protein kinase (MAPK), and cyclin-dependent kinase 5 (Cdk-5). Further studies showed that significant neuro-protection with sparing of mitochondrial function and membrane integrity could be achieved by pre-treating the cortical neurons with N-acetyl cysteine, glutathione, or inhibitors of GSK-3beta, MAP kinase, or AbetaPP gamma-secretase. Therefore, in the absence of underlying gene mutations, oxidative stress can cause AD-type abnormalities, including aberrant post-translational processing of neuronal cytoskeletal proteins and APP. Our results also suggest that pre-treatment with agents that block specific components of the AD neurodegeneration cascade may provide neuroprotection against oxidative stress-induced impairments in membrane integrity, mitochondrial function, and viability.

Author-supplied keywords

  • amyloid
  • dna damage
  • in vitro neurodegeneration model
  • kinase inhibitors
  • microtubule-associated proteins
  • mitochondria
  • neuronal death
  • s disease
  • sporadic alzheimer

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  • Guo-Jun Chen

  • Julia Xu

  • Stephanie a Lahousse

  • Niki L Caggiano

  • Suzanne M de la Monte

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