Article type: Research Article
Authors: Chen, Guo-Jun | Xu, Julia | Lahousse, Stephanie A. | Caggiano, Niki L. | de la Monte, Suzanne M.; *
Affiliations: Department of Medicine and Pathology, Rhode Island Hospital, Brown University and Brown Medical School, Providence, RI, USA
Correspondence:
[*]
Corresponding author: Dr. S.M. de la Monte, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903, USA. Tel.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: Suzanne_DeLaMonte_MD@Brown.edu.
Note: [1] Supported by Grants AA-02666, AA-02169, AA-11431 from the National Institutes of Health, COBRE Award P20RR15578, and a grant from the Panacea Corp.
Abstract: Familial Alzheimer's Disease (AD) has been linked to amyloid β protein precursor (AβPP) 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 AβPP cleavage with accumulation of Aβ-immunoreactive products. These abnormalities were associated with activation of kinases that phosphorylate tau, including glycogen synthase kinase 3β (GSK-3β), 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-3β, MAP kinase, or AβPPγ-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.
Keywords: in vitro neurodegeneration model, microtubule-associated proteins, neuronal death, mitochondria, DNA damage, kinase inhibitors, amyloid, sporadic Alzheimer's disease
DOI: 10.3233/JAD-2003-5305
Journal: Journal of Alzheimer's Disease, vol. 5, no. 3, pp. 209-228, 2003
