4.5 Review

Pathophysiological roles of amyloidogenic carboxy-terminal fragments of the,ß-Amyloid precursor protein in Alzheimer's disease

Journal

JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 97, Issue 4, Pages 461-471

Publisher

JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.CR0050014

Keywords

Alzheimer's disease; amyloid precursor protein (APP); carboxy-terminal fragment of APP; ss-amyloid

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Several lines of evidence suggest that some of the neurotoxicity in Alzheimer's disease (AD) is attributed to proteolytic fragments of amyloid precursor protein (APP) and)beta-amyloid (A,beta) may not be the sole active component involved in the pathogenesis of AD. The potential effects of other cleavage products of APP need to be explored. The CTFs, carboxyterminal fragments of APP, have been found in AD patients' brain and reported to exhibit much higher neurotoxicity in a variety of preparations than A beta. Furthermore CTFs are known to impair calcium homeostasis and learning and memory through blocking LTP, triggering a strong inflammatory reaction through MAPKs- and NF-kappa B-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus, binding with Fe65 and CP2, and in turn, affected transcription of genes including glycogen synthase kinase-3 beta which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. Spatial memory of transgenic (Tg) mice overexpressing MOO was significantly impaired and CTFs were detected in the neurons as well as in plaques of the Tg mice and double Tg mice carrying MOO and mutant tau. In this review, we summarize observations indicating that both CTF and A beta may participate in the neuronal degeneration in the progress of AD by differential mechanisms.

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