Current Alzheimer Research

Prof. Debomoy K. Lahiri  
Department of Psychiatry, Indiana University School of Medicine
Neuroscience Research Center
Indianapolis, IN 46202
USA

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Intracellular Amyloid β-Protein As a Therapeutic Target for Treating Alzheimers Disease

Author(s): Y. Ohyagi

Affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Keywords: Alzheimer's disease, amyloid β-protein, Aβ-related death-inducing protein, p53, apoptosis, proteasome

Abstract:

The amyloid cascade hypothesis is well known hypothesis describing the pathogenesis of Alzheimers disease (AD). On the basis of this hypothesis, inhibition of amyloid β-protein (Aβ) generation and aggregation, enhancement of extracellular Aβ removal, and Aβ vaccination are currently under investigation. Intracellular Aβ may be even more important than extracellular Aβ, since intraneuronal Aβ accumulation commonly precedes extracellular Aβ deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular Aβ such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. Recently, we have reported that cytosolic Aβ42 accumulation leads to p53 mRNA expression and p53-related apoptosis. It was also reported that a novel chaperone protein, Aβ-related death-inducing protein (AB-DIP), regulates nuclear localization of intracellular Aβ42. Therefore, intraneuronal Aβ represents an alternative therapeutic target. While inhibition of Aβ production and anti-Aβ immunotherapies are likely to attenuate both intraneuronal and extracellular Aβ toxicity, more specific antiintraneuronal Aβ therapies should be useful. The focus of this article is to review the pathogenic mechanisms involving intracellular Aβ and advocate intracellular Aβ as an important therapeutic target in AD.

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Article Details

VOLUME: 5
ISSUE: 6
Page: [555 - 561]
Pages: 7
DOI: 10.2174/156720508786898514