Article

The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer’s Disease and Beyond

German Center for Neurodegenerative Diseases (DZNE) Munich, Germany.
Frontiers in Physiology (Impact Factor: 3.53). 02/2012; 3:8. DOI: 10.3389/fphys.2012.00008
Source: PubMed

ABSTRACT

The β-site APP cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis and in myelination. BACE1 initiates the generation of the pathogenic amyloid β-peptide, which makes BACE1 a major drug target for AD. BACE1 also cleaves and activates neuregulin 1, thereby contributing to postnatal myelination, in particular in the peripheral nervous system. Additional proteins are also cleaved by BACE1, but less is known about the physiological consequences of their cleavage. Recently, new phenotypes were described in BACE1-deficient mice. Although it remains unclear through which BACE1 substrates they are mediated, the phenotypes suggest a versatile role of this protease for diverse physiological processes. This review summarizes the enzymatic and cellular properties of BACE1 as well as its regulation by lipids, by transcriptional, and by translational mechanisms. The main focus will be on the recent progress in understanding BACE1 function and its implication for potential mechanism-based side effects upon therapeutic inhibition.

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    • "e l s e v i e r . c o m / l o ca t e / n e u a g i n g 2006; Dislich and Lichtenthaler, 2012; Hicks et al., 2012; Vetrivel and Thinakaran, 2010). Systematic anatomic study of cases with AD-related pathology has prompted a staging classification of sporadic AD. "

    Full-text · Dataset · May 2014
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    • "Finally, we discuss the therapeutic potential of both proteases , highlight the current therapeutic development for BACE1 in Alzheimer's disease (AD) and give an outlook on future BACE protease research. Regulation of BACE protease expression and activity has been partly reviewed elsewhere (Dislich and Lichtenthaler 2012; Rossner et al. 2006) and is not the topic of this review article. b-amyloid and Alzheimer's disease AD is a devastating neurodegenerative disease characterized by the cerebral accumulation of two hallmark brain lesions: amyloid plaques and neurofibrillary tangles. "
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    ABSTRACT: The β-site APP cleaving enzymes 1 and 2 (BACE1 and BACE2) were initially identified as transmembrane aspartyl proteases cleaving the amyloid precursor protein (APP). BACE1 is a major drug target for Alzheimer's disease (AD) because BACE1-mediated cleavage of APP is the first step in the generation of the pathogenic amyloid-β peptides. BACE1, which is highly expressed in the nervous system, is also required for myelination by cleaving neuregulin 1. Several recent proteomic and in vivo studies using BACE1- and BACE2-deficient mice demonstrate a much wider range of physiological substrates and functions for both proteases within and outside of the nervous system. For BACE1 this includes axon guidance, neurogenesis, muscle spindle formation and neuronal network functions, whereas BACE2 was shown to be involved in pigmentation and pancreatic β-cell function. This review highlights the recent progress in understanding cell biology, substrates and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE inhibitors in AD.This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2014 · Journal of Neurochemistry
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    • "e l s e v i e r . c o m / l o ca t e / n e u a g i n g 2006; Dislich and Lichtenthaler, 2012; Hicks et al., 2012; Vetrivel and Thinakaran, 2010). Systematic anatomic study of cases with AD-related pathology has prompted a staging classification of sporadic AD. "
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    ABSTRACT: The presence of lipid alterations in lipid rafts from the frontal cortex in late stages of Alzheimer's disease (AD) has been recently demonstrated. Here, we have isolated and analyzed the lipid composition of lipid rafts from different brain areas from control and AD subjects at initial neuropathologic stages. We have observed that frontal cortex lipid rafts are profoundly altered in AD brains from the earliest stages of AD, namely AD I/II. These changes in the lipid matrix of lipid rafts affected both lipid classes and fatty acids and were also detected in the entorhinal cortex, but not in the cerebellum from the same subjects. Paralleling these changes, lipid rafts from AD frontal and entorhinal cortices displayed higher anisotropy for environment-sensitive probes, indicating that lipid changes in AD lipid rafts increased membrane order and viscosity in these domains. The pathophysiological consequences of these alterations in the development and progression of AD were strengthened by the significant, and specific, accumulation of β-secretase within the lipid rafts of AD subjects even at the earliest stages. Our results provide a mechanistic connection between lipid alterations in these microdomains and amyloidogenic processing of amyloid precursor protein.
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