Amyloid plaque formation

Because conformational epitopes are not easily mimicked with linear peptides, which can elicit nonspecific antibodies, several alternative strategies such as synthetic cyclic peptides have been developed [see e.g., (18)]. A similar conformational restriction was seemingly achieved with a P-amyloid peptide that was anchored to the surface of liposomes via hydrophobic tails introduced at its both N- and C-termini. The reconstituted peptide proved highly immunogenic and elicited antibodies that could significantly prevent amyloid plaque formation in a model system (70). 

Chui, D.-H., Tanahashi, H., Ozawa, K., et al. (1999) Transgenic mice with Alzheimer prese-nilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat. Med., 5, 560-564. 

Beta-amyloid peptide mRNA Block amyloid plaque formation in vitro Currie et al., 1997 Dolzhanskaya et al., 2000)... 

We tested combiBUILD by using it to help design inhibitors for cathepsin D. Cathepsin D is an aspartyl protease whose structure has been solved with the inhibitor pepstatin. It is implicated in several disease processes including Alzheimer s amyloid plaque formation and breast cancer metastasis. Our goal was to design a small library of 1000 compounds of possible inhibitors to Cathepsin D. 

We have recently found an additional amino-terminal-truncated A(3 peptide, i.e., A 52-42 in CSF of patients with AD (Wiltfang et al., 2001a), and this peptide is the second most abundant A 5 peptide in the frontal lobe of patients with AD, after A 5l-42. In the CSF, it is present in a subset of 35% of AD cases. Experimental studies with knock-out mice showed that A 52-42 was most probably produced by an alternative (3-secretase cut, and of particular pathophysiological importance is that this peptide may serve as a first nidus for 5-amyloid plaque formation (Wiltfang et al., 2001a). 

Trojanoswki, j. Q., Lee, V. M. (2001). Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. 

In addition to the traditional roles of regulators of cholinergic transmission in the serum and at the synapse, many novel roles have been proposed for ChEs (Soreq and Seidman, 2001). For example, BChE has recently been shown to attenuate amyloid plaque formation and also be involved in neurogenesis (Diamant et al, 2006 Mack and Robitzki, 2000). AChE-E has been shown to degrade heroin into 6-amino morphine, a function that AChE-S cannot perform (Salmon et al, 1999). 

Posdna R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-nietalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin hwest 113 1456-1464. 

Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, SelkoeDJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome Implications for initial events in amyloid plaque formation. Neurobiol Dis 3 16-32. 

Huang E, Buttini M, Wyss-Coray T, McConlogue L, Kodama T, Pitas RE, Mucke L (1999) Elimination of the class A scavenger receptor does not affect amyloid plaque formation or neurodegeneration in transgenic mice expressing human amyloid protein precursors. Am J Pathol 155 1741-1747. 

Mohajeri MH, Wolhner MA, Nitsch RM (2002a) Abeta 42-induced increase in neprilysin is associated with prevention of amyloid plaque formation in vivo. J Biol Chem 277 35460-35465. 

Ohno M, Hiraoka Y, Lichtenthaler SF, Nishi K, Saijo S, Matsuoka T et al (2013) Nardilysin prevents amyloid plaque formation by enhancing a-secretase activity in an Alzheimer s disease mouse model. Neurobiol Aging 35(l) 213-222... 

The importance of this substance may grow further as evidence is accumulating about the role of non-steroid anti-inflammatoiy dmg in preventing Alzheimer s disease. New results give reason to assume that some chronic inflammatoiy processes also contribute to the development of this disease. The anti-inflammatoiy effect is supplemented by an inhibition of amyloid plaque formation for certain drugs in this group (e g. ibuprofen). This effect is proven in animal tests, but human studies are not yet complete. Such an effect for oleocanthal is only assumed at this point, but its detection would explain why Alzheimer-related dementia is less common in the Mediterranean then elsewhere in Europe. 

Amino acid residues are potential targets of free radical oxidation and nitration. Carbonyl derivatives of proteins may be formed by the interaction of protein amino acid side chains, mainly cysteine, histidine, and lysine residues with reactive aldehydes, such as HNE and ONE generated by peroxidation of PUFAs (polyunsaturated fatty acids). Amino acid and peptide biomarkers of oxidative stress are typically focused on specific proteins related to disease pathology. For instance, the oxidation of histidine and methionine are typically discussed in (3-amyloid plaque formation and HNE-derived histidine adducts are the main focus of modifications on low-density lipoprotein (LDL) (An-nangudi et al., 2008). However, there are several specific examples of general biomarkers of oxidative stress that include endogenous histidine containing dipeptides such as carnosine and anserine as well as the very stable o,o -dityrosine. These will be discussed below. 

Serpell LC. Alzheimer s amyloid fibrils structure and assembly. Biochim Biophys Acta. 2000 1502(l) 16-30. Friedrich RP, Tepper K, Ronicke R, et al. Mechanism of amyloid plaque formation suggests an intracellular basis of Abeta pathogenicity. Proc Natl Acad Sci USA. 2010 107(5) 1942-1947. 

Oakley H, Cole SL, Logan S et al (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and nemon loss in transgenic mice with five familial Alzheimer s disease mutations potential factors in amyloid plaque formation. J Neurosci 26 10129-10140... 

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