BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes

Harrison, Steve; Harper, Alex; Hawkins, Julie; Dy, Graham; Grau, Evelyn; Pugh, Pippa L; Winter, Panida; Shilliam, Claire S; Hughes, Zoë A.; Dawson, Lee A.; Gonzalez, Maria; Upton, Neil; Pangalos, Menelas N.; Dingwall, Colin

doi:10.1016/s1044-7431(03)00227-6

Cited by 135 publications

(94 citation statements)

References 47 publications

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“…Previous reports claimed that genetic ablation of bace1 does not result in overt phenotypic alterations (9 -11, 39). One group reported a more timid, more anxious, and less exploratory behavior in these mice (40). In contrast, we found a complex but significant phenotype in our two independently generated bace1 knockout strains, which are characterized by increased neonatal mortality affecting up to ϳ40% of newborn animals.…”

Section: Generation and Characterization Of Bace1contrasting

confidence: 60%

Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice

Dominguez

Tournoy

Hartmann

et al. 2005

Journal of Biological Chemistry

326

345

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␤-Secretase (BACE1) is the rate-limiting protease for the generation of the amyloid ␤-peptide (A␤) in Alzheimer disease. Mice in which the bace1 gene is inactivated are reported to be healthy. However, the presence of a homologous gene encoding BACE2 raises the possibility of compensatory mechanisms. Therefore, we have generated bace1, bace2, and double knockout mice. We report here that BACE1 mice display a complex phenotype. A variable but significant number of BACE1 offspring died in the first weeks after birth. The surviving mice remained smaller than their littermate controls and presented a hyperactive behavior. Electrophysiologically, subtle alterations in the steady-state inactivation of voltage-gated sodium channels in BACE1-deficient neurons were observed. In contrast, bace2 knockout mice displayed an overall healthy phenotype. However, a combined deficiency of BACE2 and BACE1 enhanced the bace1 ؊/؊ lethality phenotype. At the biochemical level, we have confirmed that BACE1 deficiency results in an almost complete block of A␤ generation in neurons, but not in glia. As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could indeed contribute to A␤ generation in the brains of Alzheimer disease and, in particular, Down syndrome patients. In conclusion, our data challenge the general idea of BACE1 as a safe drug target and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity. Alzheimer disease (AD)1 is the most common cause of dementia for which neither a good diagnostic test nor an effective treatment is available yet. The most widely accepted hypothesis states that AD is initially triggered by the abnormal accumulation and possibly deposition of the small amyloid ␤-peptide (A␤) in different brain regions, which in turn initiates a pathogenic cascade that ultimately leads to neuronal death, AD pathology, and dementia. A␤ is cleaved from a long membranebound precursor, the amyloid precursor protein (APP), by two consecutive cleavages. ␤-and ␥-secretases are the enzymes that liberate the N and C termini of A␤, respectively, and are the subject of intense investigation because of their relevance as candidate therapeutic targets to treat AD.BACE1 and BACE2 are two highly homologous membranebound aspartyl proteases that can process APP at the ␤-secretase site (1-8). Although both enzymes exhibit many of the characteristics expected for ␤-secretase, it has been quite convincingly demonstrated that BACE1 is in fact the major ␤-secretase responsible for A␤ generation in brain (9 -11). Contrary to BACE1, BACE2 is more highly expressed in peripheral tissues, but also to some extent in brain (2,8,12,13), raising the question of whether BACE2 could contribute to the generation of the brain A␤ pool. Both BACE1 and BACE2 can cleave APP in vitro not only at Asp 1 (numbering considering the first amino acid of A␤ as position 1), but also at internal sites within the A␤ region. BACE1 cleaves between amino acids 10 and 11 o...

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Section: Generation and Characterization Of Bace1contrasting

confidence: 60%

Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice

Dominguez

Tournoy

Hartmann

et al. 2005

Journal of Biological Chemistry

326

345

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“…37 Further investigations found decreased thermal pain threshold, impaired motor coordination, myelination deficits, impaired spatial learning and memory, and altered synaptic function and neurotransmitter metabolism. [38][39][40] As a putative correlate of their learning and memory deficits, Wang et al found that activitydependent potentiation at the mossy-fiber -CA3 synapse in the hippocampus of BACE1-deficient mice is substantially impaired. 41,42 Given that AD patients, in which BACE1 activity should be elevated, often display lowered seizure threshold (see above), it appeared counterintuitive at first that BACE1 knockout mice develop epileptic seizures, too, as reported by 2 groups.…”

Section: Bace1-deficient Micementioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

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“…BACE1 knockout mice are viable and fertile and do not show any major behavioral, morphological, or developmental deficits (Cai et al 2001;Roberds et al 2001;Luo et al 2003). However, subtle behavioral phenotypes such as some memory impairment and changes in spontaneous activity (Harrison et al 2003;Dominguez et al 2005) indicate that a loss of function of BACE1 can have detrimental consequences. Very high postnatal expression levels of BACE1 (Willem et al 2006) revealed a function of BACE1 in myelination, a process which occurs after birth.…”

mentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

891

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes

Cited by 135 publications

References 47 publications

Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice

Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

Trafficking and Proteolytic Processing of APP

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