Amyloid P

Shiv]i A P, Brown F, Davies M C, Jennings K H, Roberts C J, Tendler S J B, Wilkinson M J and Williams P M 1995 Scanning tunnelling microscopy studies of p-amyloid fibril structure and assembly FEBS Lett. 371 25-8... 

General trends in radiopharmaceutical research emphasize the use of small peptides. These molecules, of which the agents mentioned for thrombosis localization are an example, exhibit rapid and specific binding, and rapid blood clearance, two important parameters for a successflil radiopharmaceutical. Peptides are readily labeled with Tc and lend themselves to formulation as lyophilized kits that can be rapidly and rehably reconstituted. Possible targets for these molecules are quite varied, ranging from atherosclerotic plaque to P-amyloid (for Alzheimer s disease), to a variety of somatic receptors the populations of which are increased or decreased in disease. 

Lyim and co-workers carried out smdies of the Ap(io 35) peptide - derived from residues 10-35 of the p-amyloid responsible for Alzheimer s disease - which forms fibrils composed of parallel p-sheets [62]. The peptide was compared to its C-terminal PEG-derivatised analogue. TEM experiments showed that both formed fibrils [63] (Fig. 21) but the uranyl acetate stain was not found inside the peptide-PEG fibrils, indicating that PEG was at the outer edge of the fibril. 

Neuritic or senile plaques are extracellular protein deposits of fibrils and amorphous aggregates of P-amyloid protein.11 This formed protein is central to the pathogenesis of AD. The P-amyloid protein is present in a non-toxic, soluble form in human brains. In AD, conformational changes occur that render it insoluble and cause it to deposit into amorphous diffuse plaques associated with dystrophic neuritis.14 Over time, these deposits become compacted into plaques and the P-amyloid protein becomes fibrillar and neurotoxic. Inflammation occurs secondary to clusters of astrocytes and microglia surrounding these plaques. 

Increased cholesterol concentrations have been associated with AD. The cholesterol increases P-amyloid protein synthesis which can lead to plaque formation.16 Also, the apo E4 allele is thought to be involved in cholesterol metabolism and is associated with higher cholesterol levels.16... 

Violette et al. (1992) have reported results implicating homeobox genes in the regulation of the gene encoding the P-amyloid precursor... 

Figure 13.6. From left to right location of the P-amyloid region of amyloid precursor protein (APP) in relation to the neuronal membrane normal processing of APP inactivates P-amyloid abnormal processing of APP in Alzheimer s disease liberates intact P-amyloid.

In 1993/1994 a series of publications caused a stir in the AD research community, since for the first time they linked a specific neuropathological process in late-onset AD to a genetic marker. Researchers looking at the composition of plaques found that the protein apolipoprotein E (ApoE) was associated with p-amyloid in the cerebrospinal fluid (CSF) of AD patients (Strittmatter et al., 1993). The gene for ApoE is on the same human chromosome (number 19) which was a risk factor in some AD pedigrees. The gene for ApoE comes in three versions (alleles) Apo s2, Apo s3 and, most importantly, Apo s4 these result in three slightly different variants of the protein. Humans carry two versions of the allele and so can have none, one or two of any of the versions of the Apo... 

Describe your understanding of the role of p-amyloid in the disease process of Alzheimer s disease. 

Amyloid protein A 42-amino acid protein found in the core of the microscopic senile plaques in the brains of individuals with Alzheimer s disease, p-amyloid protein is synthesised from the much larger amyloid precursor protein (APP). 

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... 

APP P-amyloid precursor protein 21q21 Dominant AP production (ApT AP AP ratioT)/aggregation... 

Abundant neuritic plaques and neurofibrillary lesions define Alzheimer s disease. Plaques are extracellular deposits made of the fibrillar P-amyloid peptide. The paired helical filament (PHF) makes up the bulk of the intraneuronal neurofibrillary pathology of Alzheimer s disease, with the straight filament (SF) being a minority species. 

Jankowsky, J. L., Fadale, D. J., Anderson, J. et al. Mutant presenilins specifically elevate the levels of the 42 residue P-amyloid peptide in vivo evidence for augmentation of a 42-specific y-secretase. Hum. Mol. Genet. 13 159-170, 2004. 

Chen, G., Chen, K. S., Knox, J. et al. A learning deficit related to age and P-amyloid plaques in a mouse model of Alzheimer s disease. Nature 408 975-979,2000. 

APPL P-amyloid precursor-like protein CGN cis-Golgi network... 

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