P-amyloid plaques

Carvajal FJ, Zolezzi JM, Tapia-Rojas C, Godoy JA, Inestrosa NC (2013) Tetrahydrohyperforin decreases cholinergic markers associated with amyloid-P plaques, 4-hydroxynonenal formation, and caspase-3... 

Meyer-Luehmann, M., et al. Rapid appearance and local toxicity of amyloid-P plaques in a mouse model of Alzheimer s disease. Nature 451(7179), 720-724 (2008)... 

TGF-p induces TIAFl self-aggregation via type II receptor-independent signaling that leads to generation of amyloid p plaques in Alzheimer s disease. Cell Death Dis. 2070 l(12) ell0. 

BACE-1 (p-secretase) is one of the enzymes involved in breaking down APP to produce Ap (amyloid p-peptide, Ap40>42), the protein that eventually oligomerizes to form Ap plaques, the hallmark of Alzheimer s disease (AD). Thus an agent that... 

Yang, F., Lim, G.P., Begum, A.N., et al. (2005) Curcumin inhibits formation of amyloid P oligomers and fibrils, binds plaques, and reduces amyloid in vitro. J. Biol. Chem., 280, 5892-5901. 

A similar connection between copper coordination to peptides and medical consequences exists for the Alzheimer disease.79 The amyloid-p peptide in senile plaque is the site of copper binding and as before there is interest to study details of the coordination and the stability. The neurotoxicity seems to be related to free radical damage and Cu2+ chelators are probed as therapy. So far, there seems to be no investigation at a resolution possible to pinpoint copper ligands as derived from ENDOR or related pulse techniques. We mention some relevant EPR studies as introductory sources into the topic.80 81,82... 

Fig. 7.10 The (5-sheet structure formed by the NNQQNY sequence (a) in amyloid-p proteins that leads to plaque formation [30]...

Compared with AChE in animals such as horse and rat, HA is a weaker inhibitor of human serum BuChE. This selectivity for AChE as opposed to BuChE (similar to that of galanthamine) may suggest a better side-effects profile. However, a stronger inhibition of BuChE could be important in the later stage of AD and could offer more protection over amyloid p-peptide (Ap) plaque deposition. In contrast to isoflurophate, the AChE activity did not decrease with the prolongation of incubation with HA in vitro, and the AChE activity returned to 94% of the control after being washed five times, which indicates a reversible inhibitory action. ... 

AP amyloid neuritic plaques CAA cerebral amyloid angiopathy DG Dentate gyrus DP diffuse (preamyloid) plaques NFT neurofibrillar tangles NR not reported P-Tau hyperphosphorylated MAPT tau protein. 

One might speculate that seeds arise from mutant forms of protein. For some of the discussed diseases this could be proven in cell culture models. Proteins like Huntingtin, amyloid-P and alpha-synuclein aggregate in vitro and in transfected COS cells. Models of SCA-3 show nuclear inclusions with wildtype and mutated protein [14]. Another example for this situation is found in AD plaques, where a peptide with a partial alpha-synuclein sequences seeds P-amyloid polymerization in vitro [32]. 

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. 

T. P. Kaltschmidt et al.,Transcription factor NF-Kappa B is activated in primary neurons by amyloid-P peptides and in neurons surrounding early plaques from patients with Alzheimer s disease, Proc. Natl. Acad. Sci. USA 94 ( 1997) 2642-2647. 

Handattu et al. [475] studied the effects of an ApoE mimetic peptide (Ac-hE18A-NH2) on amyloid-p pathology. Ac-hE18A-NH2 treatment improved cognition with a concomitant decrease in amyloid plaque deposition and reduced activated microglia and... 

Finally, atorvastatin effects were also examined on a class of proteins known to be involved in plaque generation and complement activation, the pentraxins. The pentraxins are acute phase proteins best exemplified by the short variants, C reactive protein and serum amyloid P [113,164]. Both are known to be closely associated with senile plaques in the brain of AD patients [113,164]. Pentraxin expression is stimulated by local inflammatory events and pentraxins are known to activate the classical complement cascade through an antibody independent mechanism [113]. Expression analysis suggest pyramidal neurons can produce amyloid P [164]. Amyloid P is highly resistant to proteolysis and binding of serum amyloid P to proteins, like AP, can protect peptides from subsequent degradation. Indeed, it is possible that serum amyloid P provides the seed for plaque formation. 

Thus, atorvastatin may have effects on inflammatory endpoints independent of cholesterol lowering. Activity on serum amyloid P could result in the lowering of plaque formation and inhibition of complement activation. 

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