Presenilin 1 and

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. 

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. 

Lleo, A., Waldron, E., von Amin, C.A.F., et al. (2005) Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for y-secretase. J. Biol. Chem., 280, 27303-27309. 

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. 

Dineley KT, Xia X, Bui D, Sweatt JD, Zheng H. Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J Biol Chem 2002 277 22,768-22,780. 

Walter, J., Grunberg, J., and Schindzielorz, A., and Haass, C, 1998, Proteolytic fragments of the Alzheimer s disease associated presenilins-1 and-2 are phosphorylated in vivo by distinct cellular mechanisms, Biochemistry 37 5961-5967. 

Kovacs DM, Fausett HJ, Page KJ, Kim TW, Moir RD, Mertiam DE, HoUister RD, Hallmark OG, Mandni R, Felsenstein KM, Hyman BT, Tanzi RE, Wasco W (1996) Alzheimer-assodated presenilins 1 and 2 neuronal expression in brain and locahzation to intracellular membranes in mammalian cells. Nat Med 2 224-229... 

Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Larmfelt L, Selkoe D, Younkin S (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer s disease. Nat Med 2 864-870. 

Taksuclii A, hizari-y MC, Duff K, Saido TC, Hsiao Aslie K, Hasegawa M, Mann DM, Hyman BT, Iwatsubo T (2000) Age-related amyloid beta deposition in tr-ansgenic mice over-expressing botli Alzheimer-mutant presenilin 1 and amyloid beta precursor protein Swedisli mutant is not associated witli global neur-onal loss. Am J Patliol 157 331-339. 

Kimberly WT, Xia WM, Rahmati R, Wolfe MS, Selkoe DJ. 2000. The transmembrane aspartates in presenilin 1 and 2 are obligatory for y-secretase activity and amyloid /3-protein generation. J. Biol. Chem. 275 3173-78... 

Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, et al. 1996. Endopro-treolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17 181-90... 

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. 

Two other genes in familial AD are presenilin 1 and 2. This form of AD affects about 10% of patients. The APOE4 gene is linked to the more widespread, late-onset disease. What the Tanzi group has done more recently is identify another gene, like APOE4, that is associated wiA an increased risk in developing AD. 

Presenilin 1 and presenilin 2 peptides H. sapiens (Synthetic) 5 mg/mL at room temperature overnight (Maury et al. 1997)... 

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