Amyloid Precursor Protein: From Synaptic Plasticity to Alzheimer's Disease

Abstract

The amyloid precursor protein (APP) has been shown to be implicated in age-associated plastic changes at synapses that might contribute to memory loss in Alzheimer's disease. As APP has previously been reported to have multiple functions during normal development, and as human and avian APP share 95% homology in amino acid sequence, we have employed a one-trial passive avoidance task in day-old chicks to study its role in the process of memory formation. Administration of anti-APP antibodies, raised against human APP, APP-antisense, and Abeta during pre-training, prevented memory formation without effects on general behavior or initial acquisition. Amnesia is apparent by 30 min post-training and lasts for at least 24 hours. Injection of APP-derived peptides RERMS (APP(328-332)) and RER (APP(328-330)) homologous to the short stretches of amino acids in the Kang sequence (APP(319-335)), rescue the memory in animals rendered amnestic by previous (anti-APP antibody, antisense, and Abeta pretreatments. The protected form of RER, with a prolonged half-life (acetylated RER), proved to be effective when injected intracranially and peripherally. The tripeptide RER exerts its biological activity by binding to two neuronal plasma membrane proteins (60 and 110 kDa). The results obtained in this study suggest that RER alleviates memory deficits via receptor-mediated events, and that short APP-derived peptides might represent a novel group of therapeutically active molecules for the alleviation of memory deficits in age-related dementias.