BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time

Amgen Inc., Thousand Oaks, CA, USA.
Neurobiology of Disease (Impact Factor: 5.2). 11/2003; 14(1):81-8. DOI: 10.1016/S0969-9961(03)00104-9
Source: PubMed

ABSTRACT The formation of Alzheimer's Abeta peptide is initiated when the amyloid precursor protein (APP) is cleaved by the enzyme beta-secretase (BACE1); inhibition of this cleavage has been proposed as a means of treating Alzheimer's disease. (AD) We have previously shown that young BACE1 knockout mice (BACE1 KO) do not generate Abeta but in other respects appear normal. Here we have extended this analysis to include both gene expression profiling and phenotypic assessment of older BACE1 KO animals to evaluate the impact of chronic Abeta deficiency. We did not detect global compensatory changes in neural gene expression in young BACE1 KO mice. In particular, expression of the beta-secretase homolog BACE2 was not upregulated. Furthermore, we found no structural alterations in any organ, including all central and peripheral neural tissues, of BACE1 KO mice up to 14 months of age. Aged BACE1 KO mice engineered to overexpress human APP (BACE1 KO/APPtg) did not develop amyloid plaques. These data provide evidence that neither beta-secretase nor Abeta plays a vital role in mouse physiology and that chronic beta-secretase inhibition could be a useful approach in treating AD.

  • Source
    • "It is well known that Ab plays a critical role in AD pathogenesis ; moreover, aggregations of Ab trigger a complex pathological cascade which leads to neurodegeneration (Golde et al., 2006). Knockout of the BACE1 gene in mice abolishes the cerebral Ab formation and amyloid deposition, and the mice were free from Alzheimer's associated pathological changes including neuronal loss and certain memory deficits (Luo et al., 2001, 2003). A further study demonstrated that the reduction of Ab levels with BACE1 gene deletion prevent memory impairment and hippocampal cholinergic dysfunction in BACE1 (À/À) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dementia is a syndrome of gradual onset and continuous decline of higher cognitive functioning. It is a common disorder in older persons and has become more prevalent today. The fresh leaves of Murraya koenigii are often added to various dishes in Asian countries due to the delicious taste and flavor that they impart. These leaves have also been proven to have health benefits. In the present study, the effect of total alkaloidal extract from M. koenigii leaves (MKA) on cognitive functions and brain cholinesterase activity in mice were determined. In vitro β-secretase 1 (BACE1) inhibitory activity was also evaluated. The total alkaloidal extract was administered orally in three doses (10, 20 and 30 mg/kg) for 15 days to different groups of young and aged mice. Elevated plus maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam-, scopolamine-, and ageing-induced amnesia served as the interoceptive behavioral models. MKA (20 and 30 mg/kg, p.o.) showed significant improvement in memory scores of young and aged mice. Furthermore, the same doses of MKA reversed the amnesia induced by scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.). Interestingly, the brain cholinesterase activity was also reduced significantly by total alkaloidal extract of M. koenigii leaves. The IC50 value of MKA against BACE1 was 1.7 μg/mL. In conclusion, this study indicates MKA to be a useful remedy in the management of Alzheimer's disease and dementia.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 11/2012; 50(3-4):1036–1044. DOI:10.1016/j.fct.2011.11.037
  • Source
    • "The type I transmembrane aspartyl proteinase -site APP cleaving enzyme (BACE1) was identified as the major -secretase for generation of A peptides by neurons (Luo et al. 2003). BACE cleaves APP at Asp1 and Glu11, whereas subsequent cleavage by -secretase gives rise to the A (1-40/42) and A (11-40/42) amyloid peptides. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of animals as models of neurodegenerative disorders has allowed the determination of biological targets and biomarkers of several diseases, has yielded new therapeutical perspectives, and is essential before performing novel clinical assays. This review discusses the nature, use, and limits of animal models and how to obtain them for several neurodegenerative disorders such as multiple system atrophy, amyotrophic lateral sclerosis, and Huntington’s disease, with a special emphasis on Parkinson’s and Alzheimer’s diseases. When possible, rodent, invertebrate and primate models are presented and discussed in relation to human disease. Finally, we highlight discrepancies between animal models and human neuropathology leading to question the pertinence of some of these findings to human disorders probably because of the wide spectrum of parameters defining a disease. Another point raised by these studies is the growing necessity to standardize the experimental procedures used to obtain an animal model, housing and breeding conditions, assessments of phenotypes investigated and, ultimately the interpretation of results obtained and their relevance to the pathology. KeywordsParkinson’s disease-Huntington disease-Alzheimer’s disease-Amyotrophic lateral sclerosis-Multiple system atrophy-Tauopathies-Nucleotide repeats
    01/2010: pages 49-101;
  • Source
    • "and do not develop AD pathology when crossed with APP transgenic mice [19]. Although the crystal structure of BACE1 has been resolved [20] [21] [22] and the enzymatic mechanism is well characterized [22], developing clinically useful inhibitors of the enzyme has proven to be difficult. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid-beta peptide (Abeta), a putatively causative agent of Alzheimer's disease (AD), is proteolytically derived from beta-amyloid precursor protein (APP). Here we describe cellular assays to detect the activity of the key protease beta-site of APP cleaving enzyme 1 (BACE1) based on an artificial reporter construct containing the BACE1 cleavage site of APP. These methods allow identification of inhibitors and indirect modulators of BACE1. In primary neuronal cultures transfected with human APP constructs (huAPP), Abeta production was modified by BACE1 inhibitors similarly to the production of endogenous murine Abeta in wild-type cells and to that of different transgenic neurons. To further improve the assay, we substituted the extracellular domain of APP by secreted alkaline phosphatase (SEAP). SEAP was easily quantified in the cell culture supernatants after cleavage of SEAP-APP by BACE1 or alpha-secretases. To render the assay specific for BACE1, the alpha-secretase cleavage site of SEAP-APP was eliminated either by site-directed mutagenesis or by substituting the transmembrane part of APP by the membrane domain of the erythropoietin receptor (EpoR). The pharmacology of these constructs was characterized in detail in HEK293 cells (human embryonic kidney cell line), and the SEAP-APP-EpoR construct was also introduced into primary murine neurons and there allowed specific measurement of BACE1 activity.
    Analytical Biochemistry 05/2009; 387(2):208-20. DOI:10.1016/j.ab.2009.01.008
Show more