Intracellular amyloid beta-protein as a therapeutic target for treating Alzheimer's disease.
The amyloid cascade hypothesis is well known hypothesis describing the pathogenesis of Alzheimer's disease (AD). On the basis of this hypothesis, inhibition of amyloid beta-protein (Abeta) generation and aggregation, enhancement of extracellular Abeta removal, and Abeta vaccination are currently under investigation. Intracellular Abeta may be even more important than extracellular Abeta, since intraneuronal Abeta accumulation commonly precedes extracellular Abeta deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular Abeta such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. Recently, we have reported that cytosolic Abeta42 accumulation leads to p53 mRNA expression and p53-related apoptosis. It was also reported that a novel chaperone protein, Abeta-related death-inducing protein (AB-DIP), regulates nuclear localization of intracellular Abeta42. Therefore, intraneuronal Abeta represents an alternative therapeutic target. While inhibition of Abeta production and anti-Abeta immunotherapies are likely to attenuate both intraneuronal and extracellular Abeta toxicity, more specific anti-intraneuronal Abeta therapies should be useful. The focus of this article is to review the pathogenic mechanisms involving intracellular Abeta and advocate intracellular Abeta as an important therapeutic target in AD.
Ohyagi
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Y
Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ohyagi@neuro.med.kyushu-u.ac.jp
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D009154:Mutation; D053763:Presenilins / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D016229:Amyloid beta-Peptides; D053763:Presenilins