Knockdown of BACE1-AS Nonprotein-Coding Transcript Modulates Beta-Amyloid-Related Hippocampal Neurogenesis (original) (raw)
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The Journal of Neuroscience, 2007
-Site amyloid precursor protein cleaving enzyme 1 (BACE1) (-secretase) initiates generation of -amyloid (A), which plays an early role in Alzheimer's disease (AD). BACE1 levels are increased in postmortem AD brain, suggesting BACE1 elevation promotes A production and AD. Alternatively, the BACE1 increase may be an epiphenomenon of late-stage AD. To distinguish between these possibilities, we analyzed BACE1 elevation using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1Ϫ/Ϫ mice, which mount a robust anti-BACE1 immune response. Previous BACE1 immunohistochemical studies lack consistent results because typical BACE1 antibodies produce nonspecific background, but BACE-Cat1 immunolabels BACE1 only. BACE1 elevation was recapitulated in two amyloid precursor protein (APP) transgenic mouse lines. 5XFAD mice form amyloid plaques at young ages and exhibit neuron loss. In contrast, Tg2576 form plaques at a more advanced age and do not show cell death. These two mouse lines allow differentiation between early A-induced events and late phenomena related to neuron death. BACE1 levels became elevated in parallel with amyloid burden in each APP transgenic, starting early in 5XFAD and late in Tg2576. The increase in BACE1 protein occurred without any change in BACE1 mRNA level, indicating a posttranscriptional mechanism. In APP transgenic and AD brains, high BACE1 levels were observed in an annulus around A42-positive plaque cores and colocalized with neuronal proteins. These results demonstrate that amyloid plaques induce BACE1 in surrounding neurons at early stages of pathology before neuron death occurs. We conclude that BACE1 elevation is most likely triggered by the amyloid pathway and may drive a positive-feedback loop in AD.
Neurobiology of Disease, 2003
The formation of Alzheimer's A peptide is initiated when the amyloid precursor protein (APP) is cleaved by the enzyme -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 A 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 A deficiency. We did not detect global compensatory changes in neural gene expression in young BACE1 KO mice. In particular, expression of the -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 -secretase nor A plays a vital role in mouse physiology and that chronic -secretase inhibition could be a useful approach in treating AD.
Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014
Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid β-peptide (Aβ) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting β-site enzyme 1 (BACE1). Because rodents do not develop amyloid pathologies, we here investigated whether AD-like endophenotypes can be created in mice by expression of human bace1. To avoid pitfalls of existing models, we introduced hbace1 via knock-in under the control of the CaMKII α promoter into the safe HPRT locus. We report amyloidogenic processing of murine APP in the hBACE1 mice (termed PLB4), resulting in the formation of toxic APP metabolites that accumulate intra- and extraneuronally in hippocampus and cortex. Pronounced accumulation of Aβ*56 and Aβ hexamers in the absence of plaque deposition was detected in brain tissue from symptomatic PLB4 mice. Heightened levels of inflammation (gliosis) also appeared in several AD-related brain regions (dentate gyrus, hip...
The number of individuals afflicted by Alzheimer’s disease (AD) worldwide is rapidly rising and we, as a society, are approaching a critical junction in the development of new therapeutics aimed at slowing or preventing the onset of this devastating neurodegenerative disease. The prevailing theory in the field pinpoints the amyloid β peptide (Aβ) as the causal agent of the disease and thus strategies that target the production, deposition, and clearance of Aβ in the brain continue to be at the forefront of therapeutic interventions. Aβ is produced through a series of proteolytic cleavage events, with β-secretase (BACE1) being the rate-limiting enzymatic activity needed to begin the liberation of the Aβ peptide from the larger amyloid precursor protein (APP). As such, BACE1 itself has become a prime therapeutic target for AD. Still, over ten years after its discovery, only a handful of compounds targeting BACE1 have reached clinical trial, indicating that complex challenges continue to persist. This short review will focus on the cellular and molecular characteristics of BACE1, its role in APP processing and in AD, and its potential as a therapeutic target for AD.
Nature Medicine, 2008
Recent transcriptomics efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for β-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. It seems that the argument for concordant regulation can only be made in the experiments with the siRNA against BACE1-AS. This convention has been followed throughout the manuscript. Please check carefully.]. Upon exposure to various cell stressors including amyloid-β 1-42 (Aβ 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Aβ 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease as well as in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Aβ 1-42 in Alzheimer's disease.
Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology
Journal of Neural Transmission, 2004
The cleavage of APP by BACE initiates the amyloidogenic process in Alzheimer's disease (AD). We have generated transgenic mice expressing BACE and double transgenic mice expressing BACE and the Swedish mutations of APP (SwAPP) in neurons. BACE transgenic mice did not develop bamyloid plaques by age of 14 months, but showed intracellular b-amyloid immunoreactivity that was co-localized with transgenic BACE in neurons. Ab levels were increased and AD-like pathology was accelerated in double transgenic mice expressing both BACE and SwAPP. At two months of age, early signs of extracellular Ab deposition and reactive astrocytes were found in double transgenic, but not in single transgenic mice. Furthermore, at four months, well defined b-amyloid deposits surrounded by activated astrocytes could be detected in the double transgenic mice. We suggest that BACE overexpression is not sufficient to produce b-amyloid plaques, but simultaneous expression of BACE and its substrate (SwAPP) leads to an accelerated amyloid plaque formation.
Human Molecular Genetics, 2001
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, β-amyloid peptides (Aβs), are produced from amyloid precursor protein (APP) by the activity of βand γ-secretases. β-secretase activity cleaves APP to define the N-terminus of the Aβ1-x peptides and, therefore, has been a longsought therapeutic target for treatment of AD. The gene encoding a β-secretase for beta-site APP cleaving enzyme (BACE) was identified recently. However, it was not known whether BACE was the primary β-secretase in mammalian brain nor whether inhibition of β-secretase might have effects in mammals that would preclude its utility as a therapeutic target. In the work described herein, we generated two lines of BACE knockout mice and characterized them for pathology, β-secretase activity and Aβ production. These mice appeared to develop normally and showed no consistent phenotypic differences from their wild-type littermates, including overall normal tissue morphology and brain histochemistry, normal blood and urine chemistries, normal blood-cell composition, and no overt behavioral and neuromuscular effects. Brain and primary cortical cultures from BACE knockout mice showed no detectable β-secretase activity, and primary cortical cultures from BACE knockout mice produced much less Aβ from APP. The findings that BACE is the primary β-secretase activity in brain and that loss of β-secretase activity produces no profound phenotypic defects with a concomitant reduction in β-amyloid peptide clearly indicate that BACE is an excellent therapeutic target for treatment of AD.
Altered Amyloid- Metabolism and Deposition in Genomic-based -Secretase Transgenic Mice
Journal of Biological Chemistry, 2004
Amyloid- (A) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by -secretase followed by ␥-secretase cleavage. Identification of the primary -secretase gene, BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering A metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating -secretase expression and activity alters APP processing and A metabolism in vivo. Genomic-based BACE1 transgenic mice were generated that overexpress human BACE1 mRNA and protein. The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing both BACE1 and APP show specific alterations in APP processing and age-dependent A deposition. We observed elevated levels of A isoforms as well as significant increases of A deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for -secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation of BACE1 activity may play a significant role in AD pathogenesis in vivo.
eNeuro
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ), one of the major pathogenic molecules of Alzheimer's disease (AD), and is therefore being actively pursued as a drug target for AD. Adult hippocampal neurogenesis (AHN) is a lifelong process that is known to be important for learning and memory and may have the potential to regenerate damaged neural tissue. In this study, we examined whether BACE1 regulates AHN, which holds important implications for its suitability as a drug target in AD. Cohorts of 2-month-old wild-type (BACE1), heterozygous, and homozygous BACE1 knockout mice (BACE1 and BACE1, respectively) were injected with 5-bromo-2'-deoxyuridine (BrdU) and sacrificed 1 day later to examine the impact of loss of BACE1 on neural precursor cell (NPC) proliferation in the adult brain. Parallel cohorts of mice were sacrificed 4 weeks after BrdU injection to determine the effects of BACE1 on survival and differentiat...