Tags

Type your tag names separated by a space and hit enter

Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease.
BMC Neurosci. 2019 Mar 20; 20(1):13.BN

Abstract

BACKGROUND

Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce Aβ without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined Aβ plaque formation and reactive gliosis in these mice.

RESULTS

In the Morris water maze, a spatial task, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-G-F/NL-G-F mice developed massive Aβ plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human Aβ40 and Aβ42 in their brains.

CONCLUSIONS

Aβ plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice.

Authors+Show Affiliations

Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan. bara@ncgg.go.jp.Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan.Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8511, Japan. iijimakm@ncgg.go.jp. Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan. iijimakm@ncgg.go.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30894120

Citation

Sakakibara, Yasufumi, et al. "Amyloid-β Plaque Formation and Reactive Gliosis Are Required for Induction of Cognitive Deficits in App Knock-in Mouse Models of Alzheimer's Disease." BMC Neuroscience, vol. 20, no. 1, 2019, p. 13.
Sakakibara Y, Sekiya M, Saito T, et al. Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease. BMC Neurosci. 2019;20(1):13.
Sakakibara, Y., Sekiya, M., Saito, T., Saido, T. C., & Iijima, K. M. (2019). Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease. BMC Neuroscience, 20(1), 13. https://doi.org/10.1186/s12868-019-0496-6
Sakakibara Y, et al. Amyloid-β Plaque Formation and Reactive Gliosis Are Required for Induction of Cognitive Deficits in App Knock-in Mouse Models of Alzheimer's Disease. BMC Neurosci. 2019 Mar 20;20(1):13. PubMed PMID: 30894120.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease. AU - Sakakibara,Yasufumi, AU - Sekiya,Michiko, AU - Saito,Takashi, AU - Saido,Takaomi C, AU - Iijima,Koichi M, Y1 - 2019/03/20/ PY - 2019/01/28/received PY - 2019/03/15/accepted PY - 2019/3/22/entrez PY - 2019/3/22/pubmed PY - 2019/8/16/medline KW - Alzheimer’s disease KW - Amyloid precursor protein KW - Cognitive deficits KW - Knock-in mouse model KW - Neuroinflammation SP - 13 EP - 13 JF - BMC neuroscience JO - BMC Neurosci VL - 20 IS - 1 N2 - BACKGROUND: Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce Aβ without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined Aβ plaque formation and reactive gliosis in these mice. RESULTS: In the Morris water maze, a spatial task, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-G-F/NL-G-F mice developed massive Aβ plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human Aβ40 and Aβ42 in their brains. CONCLUSIONS: Aβ plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice. SN - 1471-2202 UR - https://www.unboundmedicine.com/medline/citation/30894120/Amyloid_β_plaque_formation_and_reactive_gliosis_are_required_for_induction_of_cognitive_deficits_in_App_knock_in_mouse_models_of_Alzheimer's_disease_ L2 - https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-019-0496-6 DB - PRIME DP - Unbound Medicine ER -