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Plucińska K, Crouch B, Koss D, Robinson L, Siebrecht M, Riedel G, Platt B. Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. J Neurosci. 2014 Aug 6;34(32):10710-28. PubMed.
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University of California, Irvine
This study, executed by Dr. Bettina Platt's laboratory, is an important step toward understanding the role of human BACE1 in Alzheimer’s disease. It is an elegant study that provides a better understanding of the physiological role of human BACE1. In fact, our laboratory demonstrated that BACE reduction resulted in a significant decrease of soluble Aβ-oligomers, preventing the development of wild-type human tau pathology and restoring cognition (Chabrier et al., 2012). Therefore, it would be of high interest to consider BACE1 as a potential target for therapeutic intervention.
However, we need to interpret carefully the results obtained from this study. PLB4 mice present both endogenous and human BACE1. Therefore, it is possible that these mice produce more Aβ because they have more BACE1 activity; then the results of this study would not be specific to human BACE1. A good strategy to resolve this issue is to cross hBACE1 mice with BACE knockout mice.
Furthermore, BACE1 has many putative functions and substrates involved in cognitive function. Therefore, this model would be useful to determine the role of BACE1 in cognitive impairments. Obviously, Aβ is a key molecular factor that might mediate BACE1 cognitive deficits, however, BACE1 also regulates cAMP/PKA signaling and controls voltage-gated sodium channels and serotonergic transmission.
New findings reveal that BACE1 activity increases early in AD pathogenesis and it is elevated in patients with mild cognitive impairment. BACE1 appears to be an important factor for MCI patients to convert to AD (Cheng et al., 2014; Jiang et al., 2011; Zetterberg et al., 2008). Therefore, this novel model will provide a great opportunity to better understand this phenomenon.
References:
Chabrier MA, Blurton-Jones M, Agazaryan AA, Nerhus JL, Martinez-Coria H, Laferla FM. Soluble aβ promotes wild-type tau pathology in vivo. J Neurosci. 2012 Nov 28;32(48):17345-50. PubMed.
Cheng X, He P, Lee T, Yao H, Li R, Shen Y. High activities of BACE1 in brains with mild cognitive impairment. Am J Pathol. 2014 Jan;184(1):141-7. PubMed.
Jiang H, Hampel H, Prvulovic D, Wallin A, Blennow K, Li R, Shen Y. Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease. Mol Neurodegener. 2011;6:69. PubMed.
Zetterberg H, Andreasson U, Hansson O, Wu G, Sankaranarayanan S, Andersson ME, Buchhave P, Londos E, Umek RM, Minthon L, Simon AJ, Blennow K. Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch Neurol. 2008 Aug;65(8):1102-7. PubMed.
German Center for Neurodegenerative Diseases (DZNE)
I really like this paper. It shows that a mild overexpression of human BACE1 in mice can induce pathological changes similar to those seen in a human AD brain. It is amazing that the changes happen so early (behavioral and memory changes after a few months and pathology after about one year), although only endogenous APP is used. The paper is a great step toward the use of AD mouse models not overexpressing APP, and complements the recent Nat Neuroscience paper from Takaomi Saido’s lab (Saito et al., 2014).
The mouse model is a great basis for further studies. Given that BACE1 cleaves many different neuronal substrates, the authors should next cross their mouse with an APP knock-out mouse in order to figure out whether the behavioral/memory changes in their mouse are indeed only due to the increased amyloidogenic processing of APP or also due to increased cleavage of additional BACE1 substrates with brain functions. Additionally, it would be helpful if the mouse could be crossed with BACE1-deficient mice, such that only the overexpressed human BACE1 remains. Another point to study is the unexpected increase of C83. Is there really an increase in this a-secretase fragment or is this rather C89, i.e. the β-prime cleavage fragment, which results from the BACE1 cleavage site?
As an additional point: the title "Knock-in of human BACE1…." is a bit oversimplified because it suggests that human BACE1 is knocked into the mouse BACE1 locus. In fact, their mouse mildlyover expresses human BACE1 that was knocked into a specific genetic locus, but not that of murine BACE1. Thus, the mouse has both the endogenous murine BACE1 plus the transgenically expressed human BACE1.
References:
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.
University of Aberdeen
We designed this mouse to express human BACE1 in neurons at relatively low levels as a more pathophysiologically relevant model for the human condition than mice overexpressing BACE or transgenes carrying familial AD mutations. PLB4 mice develop age-associated amyloidosis, inflammation, and behaviors indicative of deficits in learning and memory, all reminiscent of early stage AD. This model can be used to examine the biology of BACE1 in the brain, and to test if and how compounds that target β-secretase modulate the disease-related phenotypes. It would be interesting now to cross PLB4 with mice expressing human APP to investigate whether offspring develop end-stage amyloid pathology, such as plaques. We also observed a subtle metabolic phenotype in these mice that requires further investigation, as do the potential differences between male and female mice.
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