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

@article{Luo2003BACE1K,
  title={BACE1 ($\beta$-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time},
  author={Yi Luo and Brad Bolon and Michael A. Damore and Dan Fitzpatrick and Hantao Liu and Jianhua Zhang and Qiao Yan and Robert J. Vassar and Martin O. Citron},
  journal={Neurobiology of Disease},
  year={2003},
  volume={14},
  pages={81-88}
}
Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice*
TLDR
Quantitative analyses indicate that brain Aβ levels in young APP transgenic mice are not the sole determinant for the changes in plaque pathology mediated by reduced BACE1, and demonstrate that partial reductions of Bace1 enzyme activity and concomitant A β levels lead to dramatic inhibition of Aβ-driven AD-like pathology.
Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice*
TLDR
The data indicate that BACE2 could indeed contribute to Aβ generation in the brains of Alzheimer disease and, in particular, Down syndrome patients and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity.
BACE1 inhibition reduces endogenous Abeta and alters APP processing in wild‐type mice 2
TLDR
The feasibility of Abeta reduction through BACE1 inhibition under physiological conditions is confirmed, and studies using the new ELISA in non‐transgenic mice provide more accurate evaluation of AbETA‐reducing strategies than was previously feasible.
Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level
TLDR
The results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower Aβ, given that Bace1 is likely to be in excess over APP in the human brain.
BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice
BACE1 structure and function in health and Alzheimer's disease.
TLDR
The basic biology of BACE1 is reviewed, focusing on the regulation, structure and function of this enzyme, and the relationship that exists between key risk factors for AD and the pathogenic alterations in Bace1 that are observed in the diseased state is discussed.
Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes
TLDR
The data argue against BACE2 being involved in the formation of neuritic plaques in AD and indicate that despite being homologous in amino acid sequence, Bace2 and BACE1 have distinct functions and transcriptional regulation.
The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease
TLDR
It is concluded that therapeutic inhibition of BACE1 should be efficacious for AD, although careful titration of the drug dose may be necessary to limit mechanism-based side effects.
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References

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BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.
TLDR
The findings that BACE is the primary beta- secretase activity in brain and that loss of beta-secretase activity produces no profound phenotypic defects with a concomitant reduction in beta-amyloid peptide clearly indicate that Bace is an excellent therapeutic target for treatment of AD.
Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation
TLDR
These results provide validation of BACE1 as the major β-secretase in vivo and suggest that therapeutic inhibition of Bace1 for the treatment of Alzheimer's disease may be free of mechanism-based toxicity.
Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes.
TLDR
Seven genes are identified that are expected to be involved in increased proteolysis, apoptosis and glial activation in neurological tissues from the knockout mice and may provide clues towards the identification of therapeutic points of intervention for EPM1 patients.
Aβ-Generating Enzymes Recent Advances in β- and γ-Secretase Research
BACE1 is the major β-secretase for generation of Aβ peptides by neurons
TLDR
It is established that BACE1 is the principal neuronal protease required to cleave APP at +1 and +11 sites that generate N-termini of Aβ.
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
TLDR
Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys670 → Asn, Met671 → Leu mutation had normal learning and memory but showed impairment by 9 to 10 months of age.
Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
TLDR
Overexpression of a transmembrane aspartic protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta- secretase positions.
Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease
TLDR
The authors' data indicate that it is full-length unmodified Aβ that accumulates initially in Tg2576 brain, and it is possible that measurement of plasma Aβ may be useful as a premorbid biomarker for AD.
γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?
TLDR
Although some data support the idea that the presenilins are in fact the active site of γ-secretase, other data indicate that they might have a more indirect role — for example, in transporting substrates to the correct subcellular compartments for ιsecretase cleavage.
Characterization of Mice Deficient in the Src Family Nonreceptor Tyrosine Kinase Frk/rak
TLDR
It is reported here that frk/rak−/− mice are viable, show similar growth rates to wild-type animals, and are fertile, demonstrating that FrK/rak is dispensable for intestinal cytodifferentiation.
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