This tendency is enchanced in the longer forms of the peptide, suggesting that these slightly larger peptides are more pathogenic (and that inhibiting fibril formation may therefore be therapeutic).11-13 Although the process in vivo is not understood, it is assumed that Aβ peptide is formed intracellularly and then aggregates either within the cell or after release into the extracellular space. However, some early work did find intracellular fibrils in cells expressing the c-terminal fragment of APP, and increasing attention is being paid to the possibility of intracellular Aβ toxicity.14-16 These

deposits of Aβ form diffuse plaques visible on immunohistochemistry in affected regions of the brain. Technically, as Inhibitors,research,lifescience,medical these diffuse plaques consist only of fibrillized extracellular peptide that is not in a beta-pleated sheet configuration and hence not biréfringent, they cannot properly Inhibitors,research,lifescience,medical be said to be amyloid. Careful studies of Down’s syndrome brains suggest a sequential series of steps whereby

diffuse plaques form the neuritic or classic plaque containing true amyloid, which in time evolves to form the burnt-out plaque where only Inhibitors,research,lifescience,medical the amyloid deposit remains.17 Understanding the process whereby Aβ is generated from APP is of the utmost importance and is the most obvious target for therapy. APP is metabolized through two opposing pathways involving three proteases.18 The first, often called the nonamyloidogenic pathway, results in cleavage of APP within the Aβ sequence moiety by the putative α-secretase. It is thought that α-secretase cleavage occurs at the extracellular membrane, but it is clear that it results in the secretion of the large extracellular portion of APP known Inhibitors,research,lifescience,medical as sAPPα.

The function of this secreted peptide is not fully understood, but α-secretase cleavage certainly prevents the formation of Aβ as the cleavage site is within this part of Inhibitors,research,lifescience,medical the protein. Although the enzyme itself has not yet been identified, the regulation of the activity of α-secretase has been extensively examined. Phorbol ester activation of protein kinase C (PKC) increases sAPPα secretion into the medium of transfected cells, and in neurons very considerably so.19-23 Entinostat Interestingly, the same observation was made when acetylcholine receptors linked through second messengers to PKC were stimulated. Stimulation of other PKC-linked receptors also stimulates sAPPα release, whereas stimulation of muscarinic receptors linked to cyclic adenosine monophosphate does not.24 These findings are intriguing and may have therapeutic significance, especially as a similarly beneficial effect of muscarinic stimulation is seen in a process thought to underlie the formation of tangles. In contrast to nonamyloidogenic processing of APP, the production of Aβ necessitates two protease best activities. The previously named enzyme β-secretase was recently identified and renamed BACE (for beta-site APP-cleaving enzyme).