Employing New Cellular Therapeutic Targets for Alzheimers Disease: A Change for the Better?

Abstract

Alzheimer's disease is a progressive disorder that results in the loss of cognitive function and memory. Although traditionally defined by the presence of extracellular plaques of amyloid-β peptide aggregates and intracellular neurofibrillary tangles in the brain, more recent work has begun to focus on elucidating the complexities of Alzheimer's disease that involve the generation of reactive oxygen species and oxidative stress. Apoptotic processes that are incurred as a function of oxidative stress affect neuronal, vascular, and monocyte derived cell populations. In particular, it is the early apoptotic induction of cellular membrane asymmetry loss that drives inflammatory microglial activation and subsequent neuronal and vascular injury. In this article, we discuss the role of novel cellular pathways that are invoked during oxidative stress and may potentially mediate apoptotic injury in Alzheimer's disease. Ultimately, targeting new avenues for the development of therapeutic strategies linked to mechanisms that involve inflammatory microglial activation, cellular metabolism, cell-cycle regulation, G-protein regulated receptors, and cytokine modulation may provide fruitful gains for both the prevention and treatment of Alzheimer's disease. Keywordsβ-Amyloid; Akt; caspases; erythropoietin; Forkhead transcription factors; metabotropic; microglia; nicotinamide; Wnt PATHOPHYSIOLOGY AND MEDICAL IMPLICATIONS OF ALZHEIMER'S DISEASENeuronal injury during Alzheimer's disease predominantly occurs in the hippocampus and the cortex. The disorder leads to a progressive deterioration of cognitive function with loss of memory and is characterized by two pathologic hallmarks that consist of extracellular plaques of amyloid-β peptide aggregates and intracellular neurofibrillary tangles composed of hyperphosphorylated microtubular protein tau. The β-amyloid deposition that constitutes the plaques is composed of a 39−42 amino acid peptide (Aβ), which is the proteolytic product of the amyloid precursor protein (APP) .With an aging population, medical costs for neurodegenerative disease parallel a progressive loss of economic productivity with increasing morbidity and mortality. The cost of physician

Driving Cellular Plasticity and Survival Through the Signal Transduction Pathways of Metabotropic Glutamate Receptors

“…Yet, what may be more interesting is the potential contribution of caspase activity during chronic neurodegeneration. Several studies support the belief that caspase activation is involved in the pathological process of chronic neurodegenerative diseases, such as AD (Chong, ZZ et al, 2005e). The elevation of caspase genes including caspase 1, 2, 3, 5, 6, 7, 8, and 9 has been observed in human postmortem brains from AD patients (Pompl, PN et al, 2003).…”

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin

“…In regards to the nervous system, cell injury related to toxin exposure (Wang et al , 2012b; Xie et al , 2012), cerebral ischemia (Chong et al , 2010a; Du et al , 2012; Li et al , 2006b; Simao et al , 2011), inflammation (Kato et al , 2011; Kigerl et al , 2012; L'Episcopo et al , 2012; Shang et al , 2009b, 2010), and Aβ exposure (Chong et al , 2005c; Lee et al , 2012; Liu et al , 2010b; Shang et al , 2012; Zeng et al , 2011) can be the result of oxidant stress. Oxidative stress in conjunction with mitochondrial dysfunction (Chong et al , 2004b; Escobar et al , 2012; Ghosh et al , 2011; Jayaram et al , 2011; Kang et al , 2003b; Maiese and Chong, 2004) can lead to neurovascular diabetic complications (Jiang et al , 2011; Maiese et al , 2008g, 2011a; Yang et al , 2011; Zengi et al , 2011), cognitive disorders (Chong et al , 2005b; Leuner et al , 2007; Maiese et al , 2009d; Zhang et al , 2011), Alzheimer's disease (AD) (Bajda et al , 2011; Maiese et al , 2009a; Srivastava and Haigis, 2011), Parkinson's disease (PD) (Asaithambi et al , 2011; Chong et al , 2005d; Khan et al , 2010; Park et al , 2011), and epilepsy (Lehtinen et al , 2009; Maiese et al , 2009c; Sales Santos et al , 2009). …”

“…In AD, Aβ is toxic to cells (Chong et al , 2005c; Echeverria et al , 2011; Kawamoto et al , 2012; Lee et al , 2012; Shang et al , 2012; Silva et al , 2011) through pathways that can involve oxidative stress (Bach et al , 2011; Bajda et al , 2011; Chong et al , 2005b, 2007a). Loss of mTOR activity in peripheral lymphocytes has a positive correlation with the progression of AD in some studies (Paccalin et al , 2006).…”

Erythropoietin: A Hormone with Multiple Functions

“…It may also be useful in the treatment of Alzheimer's disease since, as a cytoprotective agent, EPO can modulate several cellular pathways. Thus, it may provide protection against amyloid toxicity [95,96] .…”