Amyloid diseases function

The importance of cell death mediated by oxidative damage has led to the popularity of antioxidants as potential therapeutics. A variety of naturally occurring (vitamin C, vitamin E) and synthetic (lazaroids) antioxidants have been smdied as possible remedies for a wide variety of ailments. Large doses of vitamin E have been studied as a putative therapy in Alzheimer s disease, functioning through the inhibition of amyloid-induced oxidative destruction of neuronal membranes within the brain. 

The amyloidoses are a class of conformational diseases that arise from the conversion of normally unfolded or globular proteins into fibrillar aggregates that are either pathogenic or non-functional. At present there are more than 20 proteins that are associated with human amyloid diseases. This review focuses on three natively unfolded proteins that form fibrillar aggregates amyloid-, islet amyloid polypeptide ( amylin ), and a-synuclein, the diseases they contribute to and chemical and biophysical approaches that are used to investigate these proteins aggregation. 

Amyloid diseases are typically associated with aging, although some genetic neuropathy forms can begin earlier. Not yet clarified are two questions (a) what starts the accumulation of misfolded proteins that lead to the amyloidic process and (b) how do the amyloidic processes impair function of normal cells, i.e. what is the molecular mechanism of amyloid-associated cellular toxicity ... 

The failure of proteins to fold into their functional forms can occasionally lead to "misfolding" or "conformational" diseases.140 Many of these diseases are associated with the formation of amyloid protein, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. They include amyloid Ap protein as the major constituent of the plaques in Alzheimer patients, PrPc associated with neuro-degenerative diseases, a-synuclein (AS) associated with Parkinson s diseases, transthyretin (TTR) as a homotetrameric protein that is involved in the transport of thyroid hormones and retinol in human serum. In particular, the Ap protein is a peptide of 39-43 amino acids that is the... 

Alzheimer s Disease The vaccine being tested contains a small protein called jS-amyloid (AjS). This protein forms abnormal deposits, or plaques, in the brains of people with Alzheimer s disease. Researchers believe that Kji deposition causes loss of mental function by killing the brain neurons. The strategy of Aji vaccination is to stimulate the immune system to clean up plaques and prevent further A deposits. Although preclinical and Phase I studies showed the potential of the vaccine, the Phase II clinical trial was halted because 15 of 360 patients developed severe brain inflammation. Further studies showed that the A did generate the desired... 

Official Title Effect of EGb 761 on the Ratio of the Isoforms of the Protein Precursor of Beta Amyloid Platelets on Patients With Mild to Moderate Alzheimer s Disease. A Phase II, Randomized, Double-Blind Trial, on Parallel Groups Versus Placebo Primary Outcome Measures Effect of EGb 761 on the ratio of the isoform of the protein precursor of beta amyloid platelets Secondary Outcome Measures Efficacy of EGb 761 on the cognitive functions and safety of EGb 761 at a dosage of 240 mg per day Total Enrollment 40 Study Start July 2005... 

Her case is one of a great many in which some decline in optimal mental function compromises life. These compromises fall into two general categories, whose distinction may be less real than apparent. On the one hand, there are neurological diseases in which there is some detectable, definable lesion in the nervous system. In the last chapter, we met one notable example Alzheimer s disease. As mentioned then, Alzheimer s disease is characterized by amyloid plaques external to neurons and fibrillary tangles within them—clear lesions. On the other hand, there are psychiatric diseases in which the pathology is clear but for which we can detect no lesion in the nervous system. Depression and schizophrenia provide two important examples. 

A protein known as the amyloid precursor protein (APP) spans the plasma membrane of the neurone. It possesses an extracellular domain but its function is unknown. The extracellular domain is partially hydrolised by proteolytic enzymes, known as secretases. One of the products is the amyloid peptide, of which there are two forms. The larger form, contains 42 amino acids and readily polymerises to form plaques in the extracellular space, damaging the neurones. Some sufferers possess a mutated form of the APP protein which more readily produces the larger peptide upon proteolysis, so that more toxic plaques are produced. It is the progressive accumulation of these plaques that is considered to be one cause of Alzheimer s disease. 

In the early onset familial form of the disease, affecting approximately 5% of cases, there is a clear autosomal dominant pattern of inheritance. Mutations in three genes have been identified involving the beta amyloid precursor protein, presenilin-1 and presenilin-2. The function of these proteins is described in more detail in the chapter on the dementias (Chapter 14). It has been estimated that mutations in these genes account for approximately 50% of the cases of the early onset disease. 

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