Insights into oxidative stress and potential novel therapeutic targets for Alzheimer disease.
OBJECTIVE
Since the description of his original patient Auguste D. with cognitive disability, Alois Alzheimer persisted in his clinical investigations to understand this complex disease. Although more than a century later the underlying cellular dysfunctions that can initiate and determine the course of this neurodegenerative disease remain evasive, significant strides continue to elucidate the complex nature of Alzheimer dementia and define potential effective strategies for its prevention and treatment.


RESULTS
In this article, we examine the cellular mechanisms that define Alzheimer disease. They are diverse in nature and involve pathways of oxidative stress that extend well beyond the pathological hallmarks of beta-amyloid aggregates and neurofibrillary tangles. Oxidative stress precipitates both nuclear DNA degradation and membrane phosphatidylserine exposure in neuronal and vascular cells to promote loss of cellular integrity, microglial phagocytosis, and thrombotic destruction. Critical in the ability to foster cell survival during oxidative stress is the modulation of the metabotropic glutamate system, cell cycle regulation in post-mitotic neurons, and control of GSK-3beta activity and presenilin integrity. These cellular pathways ultimately converge upon more central cellular mechanisms that involve maintenance of mitochondrial membrane permeability through Bcl-2 family members, trophic factors, and mitochondrial energy reserves.


CONCLUSIONS
By targeting critical elements that determine neuronal and vascular survival during Alzheimer disease, successful development of clinical applications can emerge for the treatment of neurodegenerative disorders.
Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, MI 48201, USA. kmaiese@med.wayne.edu, aa2088@wayne.edu
Kenneth
K
Maiese
Zhao Zhong
ZZ
Chong
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
D018696:Neuroprotective Agents