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 01/2012; 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.

0 Bookmarks
 · 
116 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.
    Journal of Neuroscience 08/2014; 34(35):11621-30. · 6.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur. From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional analyses of the fusion gene products. We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1, EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. NRG1 fusions were present in 17.6% (6/34) of KRAS-negative IMAs. The CD74-NRG1 fusion activated HER2:HER3 signaling, whereas the EZR-ERBB4 and TRIM24-BRAF fusions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth/tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use. Oncogenic fusions act as driver mutations in IMAs without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such IMAs.
    Clinical Cancer Research 04/2014; · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological and observational studies indicate a positive correlation between type 2 diabetes (T2DM) and dementia, with an increased risk of dementia and Alzheimer's disease (AD) associated with insulin-treated diabetes patients. The purpose of this review is to reveal the molecular mechanisms that connect physiological and pathological processes commonly observed in T2DM and AD. Conformational modifications in peptide residues, such as amyloid-β peptide in AD and amylin in T2DM have been shown to instigate formation of insoluble protein aggregates that get deposited in extracellular spaces of brain and pancreatic tissue thus disrupting their normal function. Impaired insulin signaling plays a critical role in AD pathogenesis by reducing IRS-associated PI3 kinase activity and increasing GSK-3β activity. GSK-3β has been suggested to be a component of the γ-secretase complex and is involved in amyloid-β protein precursor processing. GSK-3β along with CDK5 is responsible for hyperphosphorylation of tau leading to the formation of neurofibrillary tangles. In summary, there is evidence to believe that a molecular link connects AD and T2DM and has potential for further investigation toward development of an effective therapeutic target.
    Journal of Alzheimer's disease: JAD 05/2014; · 3.61 Impact Factor

Preview

Download
2 Downloads
Available from