Affiliations: Division of Cellular and Molecular Cerebral Ischemia,
Wayne State University School of Medicine, Detroit, MI 48201, USA | Departments of Neurology and Anatomy & Cell
Biology, Center for Molecular Medicine and Genetics, Institute of Environmental
Health Sciences, Wayne State University School of Medicine, Detroit, MI 48201,
USA
Note: [] Corresponding author: Kenneth Maiese, MD, Department of
Neurology, 8C-1 UHC, Wayne State University School of Medicine, 4201 St.
Antoine, Detroit, MI 48201, USA. Tel.: +1 313 966 0833; Fax: +1 313 966 0486;
E-mail: kmaiese@med.wayne.edu, aa2088@wayne.edu
Abstract: Purpose: 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. Methods and 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 β-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-3β 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.
