Amyloid precursor protein mutations

Chartier-Harlin, M. C., Crawford, R, Hamandi, K., Mullan, M., Goate, A., et al. (1991) Screening for the beta-amyloid precursor protein mutation (APP717 Val— lie) in extended pedigrees with early onset Alzheimer s disease. Neurosci Lett 129, 134-135. 

Kwok JB, Li QX, HaUupp M, Whyte S, Ames D, Beyreuther K, Masters CL, Schofield PR (2000) Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol 47 249-253 LaDu MJ, Pederson TM, Frail DE, Reardon CA, Getz GS, Falduto MX (1995) Purification of apoUpoprotein E attenuates isoform-specific binding to beta-amyloid. J Biol Chem 270 9039-9042... 

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. 

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)...

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. 

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. 

Amyloid precursor protein gene (BAPP) mutations in BAPP gene itself affect BAPP protein processing, produces early onset form... 

Vercauteren, F.G., Qerens, S., Roy, L., et al. (2004) Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer s disease-finked mutations in amyloid precursor protein and presenihn-1. Brain Res. Mol. Brain Res., 132, 241-259. 

Murrell, J., Farlow, M., Ghetti, B., Benson, M.D. (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer s disease. Science, 254,97-99. 

Feng, X., Zhao, P., He, Y., Zuo, Z. (2006) AUele-specific silencing of Alzheimer s disease genes the amyloid precursor protein genes with Swedish or London mutations. Gene, 371, 68-74. 

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. 

Kumar-Singh, S., Dewachter, I., Moechars, D., Lubke, U., De Jonghe, C., et al. (2000) Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation. Neurobiol Dis 7, 9-22. 

Improvements in medication by use of acetyl cholinesterase inhibitors and general therapy significantly reduce symptoms at the onset of the disease [3, 4] but do not address the severe mortality in the final stages. A causal therapy is, therefore, still very much in demand, because no existing therapy effectively stops or even cures the disease. Identification of gene mutations linked to Alzheimer s disease-afflicted families in London and Sweden and additional polymorphisms that either cause or promote Alzheimer s disease have provided some insight into the biological pathways and the involvement of the amyloid precursor protein (APP) [5-8],... 

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