Alzheimer precursor protein

Another mechanism preventing aggregation is the immunization against aggregated protein structures. A dramatic success had been archived using this method by Schenk et al. 1999 in the case of amyloid p [81]. He was able to prevent further amyloid deposition, in older mice that already had neuritic senile plaques due to a overexpression of a mutant form of the Alzheimer precursor protein (APP) that generates high level of amyloid p. 

The protease responsible for the critical third proteolytic step is contained in a large protease complex named y-secretase (review Fortini, 2002). Proteins belonging to the presenilin family of proteases have been identified as the catalytic component of the y-secretase complex. The presenilins are transmembrane proteases with six transmembrane elements that use aspartate residues to cleave substrates. They have also been implicated in the processing of the Alzheimer precursor protein (APP), and mutations of the presenilins appear to contribute to the pathogenesis of Alzheimer s disease. In... 

Patients with Alzheimer s disease and Down syndrome have extra Alzheimer precursor proteins (APPs) in their brain as a result of mutations in the genes encoding APP. The APP gene is located on chromosome 21. Six different mutations have been identified, usually dominant. Most early onset Alzheimer s disease is caused by mutations in the presenilin 1 and presenilin 2 genes. 

A 3 amyloid is a 4 kD peptide which is the principle constituent of the Alzheimer amyloid found extracellu-larly in the brains of Alzheimer patients. A 3 amyloid is cleaved from a larger precursor protein, amyloid... 

Amyloid precursor protein (APP) is the precursor of (3-amyloid, the main component of senile plaques found in the brain of Alzheimer patients. The production of (3-amyloid from APP to the cells from abnormal proteolytic cleavage of the amyloid precursor protein. Enzymes involved in this cleavage may be suitable targets for the therapy of Alzheimer s disease. 

This type of disease occurs in families and begins unusually at early age (i.e., onset below the age of 60). Approximately 10% of Alzheimer s disease are familial and are inherited in an autosomal dominant manner with high penetrance. Deterministic genes directly cause the disease. Mutations in three different genes encoding for the amyloid precursor protein (APP) and the presenilins 1 and 2 (PS1 and PS2) have been identified to be responsible for early-onset familial Alzheimer s disease. 

Alzheimer s disease in which the pathogenicity of amyloid peptides depends on proteases, namely secretases, involved in amyloid precursor protein (APP) maturation. This chapter will describe how the proteolysis of chemokines might participate in the neuropathogenesis of HIV infection, thus contributing to the development of the central nervous system disorder termed HIV-associated dementia (HAD). 

Zhao M, Su J, Head E, Cotman CW (2003) Accumulation of caspase cleaved amyloid precursor protein represents an early neurodegenerative event in aging and in Alzheimer s disease. Neurobiol Dis 14 391-403... 

Figure 18.2 Production of senile plaque (S/A4 amyloid protein. Amyloid fS4 protein (/S/A4) is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP. This is a transmembrane protein which is normally cleared within the fi/A4 amino acid sequence to give short 40 amino-acid soluble derivatives. It seems that under some circumstances as in Alzheimer s disease, APP is cleared either side of the fi/A4 sequence to release the 42/43 amino acid P/A4 which aggregates into the amyloid fibrils of a senile plaque (a). (See also Fig. 18.5.) Some factors, e.g. gene mutation, must stimulate this abnormal clearage leading to the deposition of P/A4 amyloid protein as plaques and tangles and the death of neurons (b)...

Checler, F (1995) Processing of the /i-amyloid precursor protein and its regulation in Alzheimer s disease. J. Neurochem. 65 1431-1444. 

A universal postmortem hallmark of Alzheimer s disease (AD) is the presence of amyloid plaques in the brain. These plaques are mainly composed of a 39 to 42 amino acid peptide, referred to as A0 peptide, that is excised from a precursor protein, amyloid precursor protein (APP), by the sequential action of two proteases (Olsen et al., 2001). The first of the two cleavages of APP occurs at a site within the APP protein that is termed the P-site, and BACE has been clearly determined to be the enzyme responsible for this cleavage event. A small portion of the AD patient... 

Selkoe, D. J. (1998). The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer s disease. Trends Cell Biol. 8, 447-453. 

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.

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). 

Berezovska, O., Lleo, A., Fieri, L. D., Frosch, M. P., Stern, E. A., Bacskai, B. J. and Flyman, B. T. (2005). Familial Alzheimer s disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein. J. Neurosci. 25, 3009-17. 

Gandy, S. and Greengard, P. Processing of Alzheimer Ab-amloid precursor protein cell biology, regulation, and role in Alzheimer disease. Int. Rev. Neurobiol. 35 29-50, 1994. 

Alzheimer s disease, Parkinson s disease, Huntington s disease and amyotrophic lateral sclerosis (ALS) are four prominent fatal neurodegenerative disorders that involve the death of specific populations of neurons (see details in respective chapters). Studies of patients and animal and culture models have provided considerable insight in the cellular and molecular mechanisms responsible for synaptic dysfunction and neuronal degeneration in each disorder [18], In Alzheimer s disease, abnormalities in proteolytic processing of the amyloid precursor protein, due to gene... 

Goate,A., Chartier-Harlin,M. C.,Median,M. etal. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer s disease. Nature 349 704-706, 1991. 

Buxbaum, J. D., Thinakaran, G.,Koliatsos,V. etal. Alzheimer amyloid protein precursor in the rat hippocampus transport and processing through the perforant path. /. Neurosci. 18 9629-9637,1998. 

Sturchler-Pierrat, C., Abramowski, D., Duke, M. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Nat. Acad. Sci. USA 94 13287-13292,1997. 

Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., Luo, Y., Fisher, S., et al. (1999). Beta-secretase cleavage of Alzheimer s amyloid precursor protein by the transmembrane aspartic protease BAGE. Science 286, 735—741. 

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