β‐Amyloid Therapeutic Strategies for Alzheimer's Disease

Towards Disease-Modifying Treatment of Alzheimers Disease: Drugs Targeting β -Amyloid

“…At present, it is known that the enzyme is a member of A Disintegrin And Metalloprotease (ADAM) family of proteases and may be ADAM10, ADAM17/TACE (Tumour necrosis factor-Alpha-Converting Enzyme) [66], or even ADAM9 [67]. Structurally, ADAMs are type 1 integral membrane proteins with both a disintegrin domain and metalloprotease catalytic site [68]. Recently, studies in transgenic animals have candidated ADAM10 as the putativesecretase [69].…”

“…One possible strategy may be to upregulate ADAM10 or ADAM17/TACEsecretase gene expression. Another approach may be to use statins, retinoids or neuropeptides such as pituitary adenylate cyclase-activating polypeptide (PACAP), to stimulate secretase or PKC activities [68]. The mechanisms underlying the apparent risk reduction for AD of people taking statins are poorly understood but one hypothesis is related to the statins' ability to increase sAPP levels via -secretase acti-vation.…”

“…Whether statins act by altering the distribution of APP and the various secretases between raft and nonraft regions of the cell membranes or by altering the fluidity of the membrane is not clear. Alternatively, the expression of APP and secretases may be modified by statins [68].…”

“…Thus, enhancement of -secretase activity can be obtained by direct stimulation of PKC or by activation of receptors that work through PKC. Phorbol esters are direct PKC activators and have been shown to significantly enhance the secretion of sAPP in vitro, to reduce A in vitro and in vivo, and to prevent A toxicity in rat hippocampal neurons [68]. Unfortunately, phorbol esters are tumor promoters and therefore novel PKC activators may offer an alternative, but their safety for human use remains to be demonstrated.…”

“…A step forward in the search of potent and harmless PKC activators was made with the demonstration that bryostatin1, a macrolide lactone isolated from Bugula neritina with promising anticancer activity, was able, at sub-nanomolar concentrations, to promote sAPP secretion in fibroblasts from AD patients [77]. In addition, bryostatin1 exhibited subnanomolar affinity for PKC [68] and a 17-week intraperitoneal treatment of APP transgenic mice with 1 mg/kg of this compound produced a significant increase in brain sAPP concentrations and a decrease in brain A 40 levels [77]. Prolonged intraperitoneal treatment with bryostatin 1 (40 g/kg three times per week) of APP+PS1 double transgenic mice significantly reduced brain A 42 levels [77].…”