Alzheimers disease

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Alzheimer's disease is a neurodegenerative brain disorder causing neuronal dysfunction and ultimately cell death, giving rise to dementia. Its prevalence is increasing, as it was estimated to affect more than 10% of people over 65, or 48% of people over 85 in the US.54 The onset of Alzheimer's disease occurs with the accumulation of extra-cellular senile plaques composed of amyloid-^ (A$) peptides and with the accumulation of intercellular neurofibrillary tangles. A^ peptides are composed of a mixture of mainly 40 and 42 amino acid peptides55 and are generated from the transmembrane glycoprotein amyloid precursor protein (APP) by sequential proteolysis catalyzed by aspartyl protease ^-secretase (BACE)56 and presenilin-dependent 7-secretase.57

There are several direct roles of lithium in treatment of Alzheimer's disease. First, GSK-3 functions to phosphorylate Tau (section 1.4.1) - a process which is necessary for the accumulation of microfibrile tangles. Secondly, inhibition of GSK-a causes a reduced production of A^ peptides.58 These processes are affected at therapeutic levels of lithium. A reduction of A^ peptides is caused by the reduced processing of APP by 7-secretase, although it does not affect Notch processing, another signalling pathway modulated by this enzyme. Instead, lithium may function to modulate the access of specific substrates or the activity of these substrates towards the 7-secretase complex, a process linked to GSK-a signalling.58 Thirdly, some mutations of PS-1 are also associated with familial Alzheimer's disease, and loss of PS-1 in mice leads to increased ^-catenin protein and cell division; these results implicate PS-1 and GSK-3 in this disorder.

In addition to the direct involvement of GSK-3 in Alzheimer's disease, the neuro-protective or anti-apoptotic effects of lithium may also play a role in the treatment of Alzheimer's disease. The neuro-protective role of lithium can be clearly seen with regard to glutamate toxicity. Pretreatment of primary cere-bella granule cells with lithium gives a dose-dependent protection against this toxicity, in a concentration range that is found in patients undergoing lithium treatment. This toxicity occurs via N-methyl-D-aspartate (NMDA) receptors, as antagonists to these receptors also block toxicity. It is interesting to note that this effect is unlikely to be a direct action of lithium, as pretreatment is necessary for protection59 and this effect occurs at even lower concentrations in cortically derived neurons.60

In addition to glutamate, lithium has been shown to protect against induced apoptosis in neuronally derived cultures by a number of agents including the seizure-inducing compounds kainite,60 a-amino-3-hydroxy-5-methylisoxozole-4-propionic acid (AMPA),60 the anti-convulsants Phenytoin and CBZ61 and deprivation of high potassium and high serum.62 The broad range of compounds that lead to cell death suggests that a central signalling process is being activated in this apoptotic process and it is this common feature which is targeted by lithium. It is of considerable interest that VPA also functions to protect cerebella granule cells from glutamate exocitoxicity.60 This suggests that inositol trisphosphate depletion, which is the common action of the mood stabilizers, lithium and VPA,36 may function to prevent cell death through excitotoxicity. In support of this, pretreatment of both cerebella granule cells and cortical neurons with lithium for 7 seven days reduces the NMDA-recep-tor-mediated Ca2+ entry into cells, but does not change subunit levels.

Glycogen synthase kinase-3 may act as a modulator of apoptosis. Treatment of rat hippocampal neurons with the A^ peptide, which builds up in patients with Alzheimer's disease, both increases GSK-3^ expression and induces apoptosis.63 The apoptotic effect is blocked by antisense oligonucleotides directed at GSK-3. Wnt stimulation also protects against apoptosis, although this may be due to indirect induction of insulin-like growth factor (IGF) proteins. Insulin, IGFs, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) can all inhibit GSK-3 through activation of PI3 kinase (Figure 1.2). Inhibition of PI3 kinase, by use of chemical inhibitors or serum withdrawal, leads to increased GSK-3 activity, and this correlates with apoptosis. In addition, full GSK-3 activity requires phosphorylation at an internal tyrosine (Tyr216).64 Interestingly, it has been shown that several apoptotic stimuli induce an increase in Tyr216 phosphorylation and increase GSK-3 activity. Consistent with these observations, overexpression of GSK-3 also correlates with neuronal degeneration.65 Moderate increases in GSK-3 activity in human neuroblastoma SH-SY5Y cells did not increase the basal rate of apoptosis or caspase-3, which sits within the apoptotic signal transduction pathway, but they are associated with increased sensitivity to apoptotic stimuli. These effects are blocked by expression of the anti-apoptotic protein Bcl-2 and expression of a dominant negative form of a tumor suppressor p53. Consistent with a role of GSK-3, many of these effects can be reduced by lithium treatment.

Lithium also functions as a neuro-protective agent by altering gene transcription. P53 promotes the expression of Bax, which is a pro-apoptotic gene whose product may cause the release of cytochrome c from the mitochondria and induce subsequent caspase activation and protein degradation. Long-term lithium treatment increases p53 expression in cerebellar granule cells, as are Bax mRNA and protein levels.66 Similarly, the product of the Bcl-2 gene is a cytoprotective protein, which interacts with the mitochondrial membrane to prevent Bax-induced cytochrome c release and the induction of this apoptotic pathway. Long-term lithium treatment increases both Bcl-2 mRNA and protein levels.66 This has also been reported in rat brains following treatment with either lithium or VPA.67

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All About Alzheimers

All About Alzheimers

The comprehensive new ebook All About Alzheimers puts everything into perspective. Youll gain insight and awareness into the disease. Learn how to maintain the patients emotional health. Discover tactics you can use to deal with constant life changes. Find out how counselors can help, and when they should intervene. Learn safety precautions that can protect you, your family and your loved one. All About Alzheimers will truly empower you.

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