From Bench to Bedside: BACE1, Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1, From Basic Science to Clinical Investigation

From Bench to Bedside: BACE1, Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1, From Basic Science to Clinical Investigation

Yong Shen (Center for Advanced Therapeutic Strategies for Brain Disorders, Raskamp Institute, USA)
Copyright: © 2013 |Pages: 7
DOI: 10.4018/978-1-4666-3604-0.ch017
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Abstract

Alzheimer’s disease (AD) is a constantly progressive and highly complex neurodegenerative disease, and there are many ways to molecularly characterize the various stages. Morphologically, AD patients are characterized by neurofibrillar abnormalities associated with pathological hyperphosphorylation of tau protein, and deposits of ß– amyloid peptides (Aß). There is an overwhelming amount of information to support the hypothesis that generation, formation, and ß-amyloid deposits play key mechanistic roles in the early development of AD. It is known that the cause of early-onset familial AD (FAD) is due to mutations in three genes which cause an increase in the production of the toxic peptide, Aß42. The molecules that cause the proteolytic activities of beta and gamma secretase, two proteases that free the Aß-peptide by endoproteolyzing APP, have recently been discovered. Homologous to BACE1, BACE2 was also a recent discovery (Lin et al, 2000; Vassar et al, 1999; Yan et al, 1999), and together these two enzymes make up a new family of transmembrane aspartic proteases. The key enzyme, BACE1, initiates the formation of Aß, represents a candidate biomarker, as well as a drug target for AD, exhibit all the functional properties of ß–secretase. This chapter will review the biology of BACE1 and focus attention to BACE1 as a candidate biomarker for the early detection, prediction, and biological activity in AD.
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Iii. Pathology Of Bace1 In Ad Brains

Because BACE1 has been localized to the neurons in the brain, we can assume that they are the main source for β- amyloid peptides. Adversely, astrocytes, have been known to provide trophic support to neurons, form protective barriers between β-amyloid deposits and neurons, as well as their importance in the clearance and degradation of β- amyloid. Recently, we and two other independent research groups demonstrated an elevation of BACE1 activity in brain tissue of sporadic AD cases particularly, temporal cortex, hippocampus (Yang et al, 2003; Holsinger et al, 2002; Fukumoto et al, 2002). BACE1 mRNA is distributed in entire brain regions at moderate levels (Vassar et al, 1999; Sinha et al, 1999). Moreover, we have found that BACE1 mRNA expression levels are increased in AD brains although two recent studies (Holsinger et al, 2002; Gatta et al, 2002) failed to detect the difference in BACE1 mRNA in tissues from AD and non-demented brains. We noticed that both studies used tissues had long PMIs (> than 8 hrs). Northern blot analysis demonstrated non-differentiable or non- detectable BACE1 expression in the tissues with long PMIs. Furthermore, both studies lacked age-matched control tissues, and included a wide range of ages (from 53-86 years), as well as a wide range of MMSE scores, which might increase variability. Our laboratory has access to tissues with short PMI (<3hrs), preserving intact RNA, and a large brain bank from which to select age-matched tissue samples. Therefore, it is important to rigorously examine BACE1 mRNA in the AD and non-demented (ND) brain tissue using our technologies.

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