BACE1 partial deletion induces synaptic plasticity deficit in adult mice

Lombardo, Sylvia; Chiacchiaretta, Martina; Tarr, A.J.; Kim, WonHee; Cao, Tingyi; Sigal, Griffin; Rosahl, Thomas W.; Xia, Weiming; Kennedy, Matthew; Tesco, Giuseppina

doi:10.1038/s41598-019-56329-7

Cited by 28 publications

(26 citation statements)

References 51 publications

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“…The behavioural effects of BACEi treatment in mice presented here are similar to those reported for a conditional knockout line with BACE1 deletion in postnatal forebrain excitatory neurons (29), namely hyperactivity on the open eld, indicated by greater distance travelled, and no memory impairment in context fear conditioning or in the probe trial of the Morris water maze. Whilst no memory impairment in context fear conditioning was also observed in an adult conditional knockout with partial BACE1 deletion (30), both this study and a previous study of BACE inhibition in mice (19) report no hyperactivity on the open eld. Results from the former are in contrast to our ndings from the 15mg/kg/day BACEi cohort, with both protocols causing an ~ 50% decrease in Aβ40 brain levels in adult mice ((30), Supplementary Fig.…”

Section: Discussioncontrasting

confidence: 47%

“…Nevertheless, our results reinforce the need to examine the effect of chronic BACEi treatment on spine density and morphology with particular attention given to mushroom spine types, noting that any spine changes will vary according to neuron and dendrite type. The recently reported hippocampal long-term potentiation de cit in mice with only partial adult BACE1 deletion (30) emphasizes the importance of understanding how synaptic plasticity may be affected in patients treated with BACE inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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BACE Inhibitor Treatment in Mice Induces Hyperactivity in a Seizure-Related Gene 6 Family Protein Dependent Manner but Does Not alter Spatial Learning and Reference Memory

Nash¹,

Gijsen²,

Hrupka³

et al. 2021

Preprint

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BackgroundBACE inhibitors, which decrease BACE1 (β-secretase 1) cleavage of the amyloid precursor protein, are a potential treatment for Alzheimer’s disease. Clinical trials using BACE inhibitors have reported a lack of positive effect on patient symptoms and, in some cases, have led to increased adverse events, cognitive worsening and hippocampal atrophy. A potential drawback of this strategy is the effect of BACE inhibition on other BACE1 substrates such as Seizure-related gene 6 (Sez6) family proteins which are known to have a role in neuronal function.MethodsMice were treated with an in-diet BACE inhibitor for 4-8 weeks to achieve a clinically-relevant level of amyloid-β40 reduction in the brain. Mice underwent behavioural testing and postmortem analysis of dendritic spine number and morphology with Golgi-Cox staining. Sez6 family triple knockout mice were tested alongside wild-type mice to identify whether any effects of the treatment were due to altered cleavage of Sez6 family proteins.ResultsWild-type mice treated with BACE inhibitor displayed hyperactivity on the elevated open field, as indicated by greater distance travelled, but this effect was not observed in treated Sez6 triple knockout mice. BACE inhibitor treatment did not lead to significant changes in spatial or fear learning, reference memory, cognitive flexibility or anxiety in mice as assessed by the Morris water maze, context fear conditioning, or light-dark box tests. Chronic BACE inhibitor treatment reduced the density of mushroom-type spines in the somatosensory cortex, regardless of genotype, but did not affect steady-state dendritic spine density or morphology in the CA1 region of the hippocampus. ConclusionsChronic BACE inhibition for 1-2 months in mice led to increased locomotor output but did not alter memory or cognitive flexibility. While the mechanism underlying the treatment-induced hyperactivity is unknown, the absence of this response in Sez6 triple knockout mice indicates that blocking ectodomain shedding of Sez6 family proteins is a contributing factor. In contrast, the decrease in mature spine density in cortical neurons was not attributable to lack of shed Sez6 family protein ectodomains. Therefore, other BACE1 substrates are implicated in this effect and, potentially, in the cognitive decline in longer-term chronically treated patients.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

BACE Inhibitor Treatment in Mice Induces Hyperactivity in a Seizure-Related Gene 6 Family Protein Dependent Manner but Does Not alter Spatial Learning and Reference Memory

Nash¹,

Gijsen²,

Hrupka³

et al. 2021

Preprint

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“…( 98 ) reported impairment of LTP in CA1 of conditional BACE1-deficient mice, whereas CA1 LTP was reported to be normal in a different BACE1 cKO mouse model ( 99 ). However, we showed that CA1 LTP was impaired in BACE1 cKO mice with a partial reduction of BACE1 (∼50% to ∼70%) ( 100 ). Thus, BACE1-dependent imbalance of PSA-NCAM1 could be the underlying mechanism of the abnormal LTP in CA1 in BACE1−/− and BACE1 cKO mice.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

Kim

Watanabe

Lomoio

et al. 2021

Journal of Biological Chemistry

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Neural cell adhesion molecules 1 (NCAM1) and 2 (NCAM2) belong to the cell adhesion molecules of the immunoglobulin superfamily and have been shown to regulate formation, maturation, and maintenance of synapses. NCAM1 and NCAM2 undergo proteolysis, but the identity of all the proteases involved and how proteolysis is used to regulate their functions are not known. We report here that NCAM1 and NCAM2 are BACE1 substrates in vivo . NCAM1 and NCAM2 overexpressed in HEK cells were both cleaved by metalloproteinases or BACE1, and NCAM2 was also processed by γ-secretase. We identified the BACE1 cleavage site of NCAM1 (at Glu 671) and NCAM2 (at Glu 663) using mass spectrometry and site-directed mutagenesis. Next, we assessed BACE1-mediated processing of NCAM1 and NCAM2 in the mouse brain during aging. NCAM1 and NCAM2 were cleaved in the olfactory bulb of BACE1+/+ but not BACE1−/− mice at postnatal day 10 (P10), 4 and 12 months of age. In the hippocampus, a BACE1-specific soluble fragment of NCAM1 (sNCAM1β) was only detected at P10. However, we observed an accumulation of full-length NCAM1 in hippocampal synaptosomes in 4-month-old BACE1−/− mice. We also found that polysialylated NCAM1 (PSA-NCAM1) levels were increased in BACE1−/− mice at P10 and demonstrated that BACE1 cleaves both NCAM1 and PSA-NCAM1 in vitro . In contrast, we did not find evidence for BACE1-dependent NCAM2 processing in the hippocampus at any age analyzed. In summary, our data demonstrate that BACE1 differentially processes NCAM1 and NCAM2 depending on the region of brain, subcellular localization, and age in vivo .

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“…Indeed, the extracellular concentration of Aβ increases after neuronal stimulation [123,253] and interstitial fluid Aβ concentration positively correlates with neuronal activity in human brain [29]. Interestingly, both APP knockout [53] and BACE1 knockout [139,154,272,273] in vivo induce cognitive deficits and impair LTP. Wild-type mice given BACE1 inhibitors also show a dose-dependent suppression of LTP and impaired cognitive performance [74].…”

Section: Physiological Concentrations Of Aβ Enhance Ltpmentioning

confidence: 99%

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

2020

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Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become the focus of therapeutic development. Recent research, however, shows that these proteins have been highly conserved throughout evolution and may have crucial, physiological roles. Such functions may be lost during AD progression or be unintentionally disrupted by tau- or Aβ-targeting therapies. Tau has been revealed to be more than a simple stabiliser of microtubules, reported to play a role in a range of biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning and memory, neuronal excitability, and DNA protection. Aβ is similarly multifunctional, and is proposed to regulate learning and memory, angiogenesis, neurogenesis, repair leaks in the blood–brain barrier, promote recovery from injury, and act as an antimicrobial peptide and tumour suppressor. This review will discuss potential physiological roles of tau and Aβ, highlighting how changes to these functions may contribute to pathology, as well as the implications for therapeutic development. We propose that a balanced consideration of both the physiological and pathological roles of tau and Aβ will be essential for the design of safe and effective therapeutics.

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BACE1 partial deletion induces synaptic plasticity deficit in adult mice

Cited by 28 publications

References 51 publications

BACE Inhibitor Treatment in Mice Induces Hyperactivity in a Seizure-Related Gene 6 Family Protein Dependent Manner but Does Not alter Spatial Learning and Reference Memory

BACE Inhibitor Treatment in Mice Induces Hyperactivity in a Seizure-Related Gene 6 Family Protein Dependent Manner but Does Not alter Spatial Learning and Reference Memory

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

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