Novel therapeutics for Alzheimer's disease: an update.

As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a significant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease.

Treatment advances in Alzheimer's disease based on the oxidative stress model.

Effective therapy for Alzheimer's disease (AD), up to this point, has been hampered by our inability to diagnose the disease in its early stages, before the occurrence of significant neurodegeneration and clinical symptoms. Because AD historically has been defined by neuropathologic criteria, treatment strategies have been aimed at diminishing the pathologic end result of the disease process, namely neurodegenerative changes associated with extracellular amyloid-beta-containing plaques, as well as intracellular neurofibrillary tangles of the hyper-phosphorylated microtubule protein, tau. While these avenues continue to be pursued, results thus far have been disappointing.

L-arginine and Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive neurodegeneration and loss of cognitive and memory functions. Although the exact causes of AD are still unclear, evidence suggests that atherosclerosis, redox stress, inflammation, neurotransmitter dysregulation, and impaired brain energy metabolism may all be associated with AD pathogenesis. Herein, we explore a possible role for L-arginine (L-arg) in AD, taking into consideration known functions for L-arg in atherosclerosis, redox stress and the inflammatory process, regulation of synaptic plasticity and neurogenesis, and modulation of glucose metabolism and insulin activity.

Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease.

The essential metals iron, zinc and copper deposit near the Abeta (amyloid beta-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid Abetas, which exhibit metal-catalysed neurotoxicity.

Alzheimer disease beta-amyloid activity mimics cholesterol oxidase.

The abnormal accumulation of amyloid beta-peptide (Abeta) in the form of senile (or amyloid) plaques is one of the main characteristics of Alzheimer disease (AD). Both cholesterol and Cu2+ have been implicated in AD pathogenesis and plaque formation. Abeta binds Cu2+ with very high affinity, forming a redox-active complex that catalyzes H2O2 production from O2 and cholesterol.

Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal beta-amyloid deposition is dependent on the activity of zinc transporter 3 (ZnT3), a neocortical synaptic vesicle membrane protein that causes enrichment of exchangeable Zn2+ in the vesicle, which is externalized on neurotransmission. However, the contribution of zinc to vascular beta-amyloid deposition remains unclear.

BCL-2 improves oxidative phosphorylation and modulates adenine nucleotide translocation in mitochondria of cells harboring mutant mtDNA.

Members of the BCL-2-related antiapoptotic family of proteins have been shown previously to regulate ATP/ADP exchange across the mitochondrial membranes and to prevent the loss of coupled mitochondrial respiration during apoptosis. We have found that BCL-2/BCL-x(L) can also improve mitochondrial oxidative phosphorylation in cells harboring pathogenic mutations in mitochondrial tRNA genes. The effect of BCL-2 overexpression in mutated cells was independent from apoptosis and was presumably associated with a modulation of adenine nucleotide exchange between mitochondria and cytosol.