Deposition Amyloid

Most cases of AzD show cerebrovascular amyloid deposits and the amyloid protein of senile plaques is the same as that found in blood vessels. It is referred to as )S-amyloid protein and is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP, which is a transmembrane protein and although its precise function is not clear, it is widely distributed and APP knock-out mice show reduced motor function. Normally so-called short 40 amino-acid-soluble derivatives of APP are produced by proteolytic cleavage of APP within the j] (A4) amino-acid sequence but APP can also be cleaved... 

In fact no consistent correlation has been found between the appearance, distribution and number of amyloid plaques and either neuronal loss or the degree of dementia, although the latter correlates with the number of neurofibrillary tangles, which tend to precede plaques in appearance by some years. Also cortical amyloid deposits can be found in non-demented elderly patients. Thus the basic question appears to be does the disease process, whatever that is, cause the development of AzD as well as the production of jS-amyloid or is there production of S-amyloid, which then causes AzD Consensus supports the latter but it is not proven. 

A number of family mutations of the APP gene on chromosome 21 have been found, generally in early-onset AzD patients in different countries, all of which lead to increased jS-amyloid production. Also chromosome 21 is abnormally trisomic in Down Syndrome and most Down sufferers develop AzD if they reach 40 years. In transgenic mice, expressing familial AzD mutations of APP, the overexpression of APP is accompanied by increased amyloid deposition but whether this is due to the mutation or overexpression of APP is uncertain. Also not all the animals show memory loss and that tends to precede the amyloid disposition. 

Thus all the above genetic mutations can lead to increased amyloid deposition and possibly AzD (see Smith 1998). Unfortunately familial AzD represents only the minority of cases and so other causes need to be considered. 

It has been estimated that up to 15% of head injuries may lead to AzD with dementia being common among boxers dementiapugilistica). Certainly such trauma is associated with diffuse amyloid deposits (not plaques) and a number of neurofibrillary tangles apparently identical to those in AzD. 

CF-related diabetes shares characteristics of both type 1 and type 2 diabetes mellitus but is categorized separately. The primary cause of CFRD is insulin deficiency resulting from both reduced functional pancreatic islet cells and increased islet amyloid deposition. Insulin secretion is delayed in response to glucose challenge, and absolute insulin secretion over time is reduced. Some insulin resistance may also be present in CFRD however, sensitivity may be increased in CF patients without diabetes.8... 

Another prominent site of deposition of (5-amyloid fibrils with age and in AD is within the cerebrovasculature in areas of the brain prone to parenchymal amyloid deposition [137-139]. The peptide deposits along the surfaces of the smooth muscle cells of the vascular wall, resulting in the death of those cells and their replacement by amyloid fibrils, weakening the vascular wall. Endothelial cells are also affected [140]. The Dutch mutation in the APP precursor protein Q22E, within the (5-peptide sequence, produces a particularly fibrillogenic and toxic (to smooth muscle cells) peptide associated with primarily vascular deposition of mutant peptide and hemorrhagic vessel disease [137]. Thus, in addition to neuronal cells, the brain vascular smooth muscle cells are a pathologically relevant cell type. While the source of... 

Roher AE, Chaney MO, Kuo YM, Webster SD, Stine WB, Haverkamp LJ, Woods AS, Cotter RJ, Tuohy JM, Krafft GA, Bonnell BS, Emmerling MR. Morphology and toxicity of Abeta-(l-42) dimer derived from neuritic and vascular amyloid deposits of Alzheimer s disease. J Biol Chem 1996 ... 

Human amylin, or islet amyloid polypeptide (hlAPP), is a 37-residue peptide hormone which forms both intracellular and extracellular (EC) amyloid deposits in the pancreas of most type II diabetic subjects. The core of the structure in the SDS micelle is an ot-helix that runs from about residues 5-28. Although the basic structural unit in the fibrils in... 

Rocken C, Roessner A. An evaluation of antigen retrieval procedures for immu-noelectron microscopic classification of amyloid deposits. J. Histochem. Cytochem. 1999 47 1385-1394. 

Alzheimer s disease is the most common form of age-related dementia and one of the most serious health problems in the industrialized world. AD is an insidious and progressive neurodegenerative disorder that accounts for the vast majority of dementia and is characterized by global cognitive decline and the accumulation of P-amyloid deposits and neurofibrillary tangles in the brain. Family history is the second greatest risk factor for... 

Borchelt, D. R., Ratovitski, T., Van Lare, J. et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19 939-945,1997. 

The term amyloidosis is associated with a heterogeneous group of protein-folding disorders. These diseases, like type 2 diabetes and Alzheimer s disease, are characterized by the presence of macroscopic abnormalities, amyloid deposits, in one or more organs of the patients. The proteins or protein fragments accumulated in these deposits belong to three main... 

Additional factors may influence fibril stability in vivo. The glycan molecules and amyloid P component found in amyloid deposits may stabilize amyloid fibrils (Pepys, 2006, and references therein). Also, monomer concentration is important to amyloid formation and stability in vivo several amyloidoses are associated with elevated levels of the fibril precursor protein, and deposits regress when the levels of the precursor protein are sufficiently reduced (Pepys, 2006, and references therein). 

Halverson, K., Fraser, P. E., Kirschner, D. A., and Lansbury, P. T., Jr. (1990). Molecular determinants of amyloid deposition in Alzheimer s disease Conformational studies of synthetic beta-protein fragments. Biochemistry 29, 2639-2644. 

Fig. 18 Chemical structure of (a) PTAA, (b) PONT and (c) POMT. (d, e) Fluorescence images of amyloid deposits in tissue stained by PTAA. PTAA bound to amyloid deposits (white arrows) emits light with a yellow-red, color [33]...

Nilsson KPR, Hammarstrdm P, Ahlgren F, Herland A, Schnell EA, Lindgren M, Westermark GT, Inganas O (2006) Conjugated polyelectrolytes-conformation-sensitive optical probes for staining and characterization of amyloid deposits. Chem Bio Chem 7 1096-1104... 

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