Luo, Y. et al. BACE1 (-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol. Dis. 14, 81-88
Amgen Inc., Thousand Oaks, CA, USA. Neurobiology of Disease
(Impact Factor: 5.08).
11/2003; 14(1):81-8. DOI: 10.1016/S0969-9961(03)00104-9
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.
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Available from: Morgan Newman
- "Inhibition of β-secretase, also known as beta-site APP cleaving enzyme (BACE1), is of prime interest for the development of amyloid-lowering drugs. BACE1 has become an attractive target for drug development as, in comparison to the lethality observed in Psen1 null mice, Bace1 knock-out mice are viable (Roberds et al., 2001; Luo et al., 2003) and have subtle phenotypes (Harrison et al., 2003; Willem et al., 2006). Furthermore no phenotypes have been reported for knockout of the Bace1 homolog, Bace2 and deletion of Bace2 in mice did alter Aβ generation (Dominguez et al., 2005). "
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ABSTRACT: Rodent models have been extensively used to investigate the cause and mechanisms behind Alzheimer's disease. Despite many years of intensive research using these models we still lack a detailed understanding of the molecular events that lead to neurodegeneration. Although zebrafish lack the complexity of advanced cognitive behaviors evident in rodent models they have proven to be a very informative model for the study of human diseases. In this review we give an overview of how the zebrafish has been used to study Alzheimer's disease. Zebrafish possess genes orthologous to those mutated in familial Alzheimer's disease and research using zebrafish has revealed unique characteristics of these genes that have been difficult to observe in rodent models. The zebrafish is becoming an increasingly popular model for the investigation of Alzheimer's disease and will complement studies using other models to help complete our understanding of this disease.
Available from: Alfredo Kirkwood
- "Because γ-secretase also has other physiological functions critical for normal cell development , , β-secretase inhibition has surfaced as a more attractive therapeutic option , –. However, many recent studies, including our own, have shown that although BACE1 knockouts (KOs) lack Aβ peptides  and show no gross anatomical or functional abnormalities , , they display specific synaptic dysfunctions in the CA1 and CA3 regions of the hippocampus –. In particular, BACE1 KOs showed presynaptic dysfunctions at the mossy fiber (MF) to CA3 synapses, which is one of the major loci of BACE1 expression in the brain . "
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ABSTRACT: Beta-amyloid precursor protein cleaving enzyme 1 (BACE1), a major neuronal β-secretase critical for the formation of β-amyloid (Aβ) peptide, is considered one of the key therapeutic targets that can prevent the progression of Alzheimer's disease (AD). Although a complete ablation of BACE1 gene prevents Aβ formation, we previously reported that BACE1 knockouts (KOs) display presynaptic deficits, especially at the mossy fiber (MF) to CA3 synapses. Whether the defect is specific to certain inputs or postsynaptic targets in CA3 is unknown. To determine this, we performed whole-cell recording from pyramidal cells (PYR) and the stratum lucidum (SL) interneurons in the CA3, both of which receive excitatory MF terminals with high levels of BACE1 expression. BACE1 KOs displayed an enhancement of paired-pulse facilitation at the MF inputs to CA3 PYRs without changes at the MF inputs to SL interneurons, which suggests postsynaptic target specific regulation. The synaptic dysfunction in CA3 PYRs was not restricted to excitatory synapses, as seen by an increase in the paired-pulse ratio of evoked inhibitory postsynaptic currents from SL to CA3 PYRs. In addition to the changes in evoked synaptic transmission, BACE1 KOs displayed a reduction in the frequency of miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) in CA3 PYRs without alteration in mEPSCs recorded from SL interneurons. This suggests that the impairment may be more global across diverse inputs to CA3 PYRs. Our results indicate that the synaptic dysfunctions seen in BACE1 KOs are specific to the postsynaptic target, the CA3 PYRs, independent of the input type.
Available from: link.springer.com
- "As an additional negative control, we immunostained sections from a 9 month-old 5XFAD; BACE1−/− mouse and observed no Aβ42 labeling (Figure 3E). Importantly, the lack of Aβ42 signal in 5XFAD; BACE1−/− brain sections validated the selectivity of our anti-Aβ42 antibody, confirming that the antibody did not cross-react with full length APP or APP C-terminal fragments, and verified that plaque deposition requires BACE1 activity, as previously shown [17-20]. Together, these observations demonstrate that the regions with the greatest age-related Aβ42 deposition are also the same regions that exhibit neuron loss in 5XFAD brain. "
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Although the mechanism of neuron loss in Alzheimer’s disease (AD) is enigmatic, it is associated with cerebral accumulation of Aβ42. The 5XFAD mouse model of amyloid deposition expresses five familial AD (FAD) mutations that are additive in driving Aβ42 overproduction. 5XFAD mice exhibit intraneuronal Aβ42 accumulation at 1.5 months, amyloid deposition at 2 months, and memory deficits by 4 months of age.
Here, we demonstrate by unbiased stereology that statistically significant neuron loss occurs by 9 months of age in 5XFAD mice. We validated two Aβ42-selective antibodies by immunostaining 5XFAD; BACE1−/− bigenic brain sections and then used these antibodies to show that intraneuronal Aβ42 and amyloid deposition develop in the same regions where neuron loss is observed in 5XFAD brain. In 5XFAD neuronal soma, intraneuronal Aβ42 accumulates in puncta that co-label for Transferrin receptor and LAMP-1, indicating endosomal and lysosomal localization, respectively. In addition, in young 5XFAD brains, we observed activated Caspase-3 in the soma and proximal dendrites of intraneuronal Aβ42-labeled neurons. In older 5XFAD brains, we found activated Caspase-3-positive punctate accumulations that co-localize with the neuronal marker class III β-tubulin, suggesting neuron loss by apoptosis.
Together, our results indicate a temporal sequence of intraneuronal Aβ42 accumulation, Caspase-3 activation, and neuron loss that implies a potential apoptotic mechanism of neuron death in the 5XFAD mouse.
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