BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory

Abstract BACE 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 adv...

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Autores principales:	A. Nash, H. J. M. Gijsen, B. J. Hrupka, K. S.-L. Teng, S. F. Lichtenthaler, H. Takeshima, J. M. Gunnersen, K. M. Munro
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/30fc73a123fe4f83943a0c12121c8a83
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spelling	oai:doaj.org-article:30fc73a123fe4f83943a0c12121c8a832021-12-02T16:26:30ZBACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory10.1038/s41598-021-94369-02045-2322https://doaj.org/article/30fc73a123fe4f83943a0c12121c8a832021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94369-0https://doaj.org/toc/2045-2322Abstract BACE 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. Mice 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. Wild-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. Chronic 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.A. NashH. J. M. GijsenB. J. HrupkaK. S.-L. TengS. F. LichtenthalerH. TakeshimaJ. M. GunnersenK. M. MunroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q A. Nash H. J. M. Gijsen B. J. Hrupka K. S.-L. Teng S. F. Lichtenthaler H. Takeshima J. M. Gunnersen K. M. Munro BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory
description	Abstract BACE 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. Mice 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. Wild-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. Chronic 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.
format	article
author	A. Nash H. J. M. Gijsen B. J. Hrupka K. S.-L. Teng S. F. Lichtenthaler H. Takeshima J. M. Gunnersen K. M. Munro
author_facet	A. Nash H. J. M. Gijsen B. J. Hrupka K. S.-L. Teng S. F. Lichtenthaler H. Takeshima J. M. Gunnersen K. M. Munro
author_sort	A. Nash
title	BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory
title_short	BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory
title_full	BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory
title_fullStr	BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory
title_full_unstemmed	BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory
title_sort	bace inhibitor treatment of mice induces hyperactivity in a seizure-related gene 6 family dependent manner without altering learning and memory
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/30fc73a123fe4f83943a0c12121c8a83
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BACE inhibitor treatment of mice induces hyperactivity in a Seizure-related gene 6 family dependent manner without altering learning and memory

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