One of the earliest cellular alterations in Alzheimer’s disease is an intracellular accumulation of amyloid-β (Aβ), generated by altered processing of the amyloid precursor protein (APP) by β- and γ-secretases. However, APP also produces other fragments, including the neurotrophic and neuroprotective secreted form of APPα (sAPPα), generated by α-secretase activity. The sAPP contributes to normal memory function and its role as a key contributor to synaptic plasticity is supported by experimental findings showing that exogenous administration of sAPPα or small peptide fragments derived from its amino acid sequence enhance memory performance in mice, rats and chicks. Although birds and mammals diverged about 270 million years ago, the chick APP gene sequence and enzymatic machinery for processing APP is almost identical to that of humans. The chick is thus a useful natural model in which to study the cell biology and developmental function of APP and a potential “assay system” for drugs that regulate APP processing. Using a one-trial passive avoidance task in day-old chicks, we reported that the amnestic effect of pre-training injections of anti-APP antibody or APP-antisense could be prevented by intracerebral injection of the pentapeptide RERMS, homologous to APP322-328, part of the growth-promoting E2 domain of sAPP. Subsequently, we have shown that this effect is due to the palindromic tripeptide sequence RER. Injected intracerebrally around the time of training, RER not only protects against the amnestic effects of downregulating or functionally blocking APP, but also against the amnestic effect of the Aβ1-42. To both cast light on the mode of action of the peptide, and to increase its efficacy as a potential memory enhancer, we have examined the behavioural responses in chick to the optically isomeric D- or diasteromeric (D/L) forms of the peptide as arginine-rich peptides easily cross cell membranes and bind to membrane-associated and cytoplasmic proteoglycans. One of them, acetylated- rER (Ac-rER, where the lower case indicates the D-isomeric form of the amino acid), is rapidly transported across the blood-brain-barrier, protects against Aβ-induced memory loss and enhances retention when injected peripherally up to 12 hr prior to training. Therefore, we propose that RER-related peptides may form the basis for a potential therapeutic agent in the early stages of Alzheimer’s disease.
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