Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer's disease

analysis of Osaka mutation-knockin mice

Tomohiro Umeda, Tetsuya Kimura, Kayo Yoshida, Keizo Takao, Yuki Fujita, Shogo Matsuyama, Ayumi Sakai, Minato Yamashita, Yuki Yamashita, Kiyouhisa Ohnishi, Mamiko Suzuki, Hiroshi Takuma, Tsuyoshi Miyakawa, Akihiko Takashima, Takashi Morita, Hiroshi Mori, Takami Tomiyama

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

Original languageEnglish
Number of pages1
JournalActa neuropathologica communications
Volume5
Issue number1
DOIs
Publication statusPublished - 31-07-2017

Fingerprint

Amyloid beta-Protein Precursor
Homozygote
Alzheimer Disease
Mutation
Picrotoxin
Synapses
Heredity
Neuronal Plasticity
Long-Term Potentiation
Electrophysiology
Memory Disorders
Interneurons
Heterozygote
Diazepam
Amyloid
Neuroglia
gamma-Aminobutyric Acid
Oral Administration
Dementia
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Umeda, Tomohiro ; Kimura, Tetsuya ; Yoshida, Kayo ; Takao, Keizo ; Fujita, Yuki ; Matsuyama, Shogo ; Sakai, Ayumi ; Yamashita, Minato ; Yamashita, Yuki ; Ohnishi, Kiyouhisa ; Suzuki, Mamiko ; Takuma, Hiroshi ; Miyakawa, Tsuyoshi ; Takashima, Akihiko ; Morita, Takashi ; Mori, Hiroshi ; Tomiyama, Takami. / Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer's disease : analysis of Osaka mutation-knockin mice. In: Acta neuropathologica communications. 2017 ; Vol. 5, No. 1.
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abstract = "The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.",
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Umeda, T, Kimura, T, Yoshida, K, Takao, K, Fujita, Y, Matsuyama, S, Sakai, A, Yamashita, M, Yamashita, Y, Ohnishi, K, Suzuki, M, Takuma, H, Miyakawa, T, Takashima, A, Morita, T, Mori, H & Tomiyama, T 2017, 'Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer's disease: analysis of Osaka mutation-knockin mice', Acta neuropathologica communications, vol. 5, no. 1. https://doi.org/10.1186/s40478-017-0461-5

Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer's disease : analysis of Osaka mutation-knockin mice. / Umeda, Tomohiro; Kimura, Tetsuya; Yoshida, Kayo; Takao, Keizo; Fujita, Yuki; Matsuyama, Shogo; Sakai, Ayumi; Yamashita, Minato; Yamashita, Yuki; Ohnishi, Kiyouhisa; Suzuki, Mamiko; Takuma, Hiroshi; Miyakawa, Tsuyoshi; Takashima, Akihiko; Morita, Takashi; Mori, Hiroshi; Tomiyama, Takami.

In: Acta neuropathologica communications, Vol. 5, No. 1, 31.07.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer's disease

T2 - analysis of Osaka mutation-knockin mice

AU - Umeda, Tomohiro

AU - Kimura, Tetsuya

AU - Yoshida, Kayo

AU - Takao, Keizo

AU - Fujita, Yuki

AU - Matsuyama, Shogo

AU - Sakai, Ayumi

AU - Yamashita, Minato

AU - Yamashita, Yuki

AU - Ohnishi, Kiyouhisa

AU - Suzuki, Mamiko

AU - Takuma, Hiroshi

AU - Miyakawa, Tsuyoshi

AU - Takashima, Akihiko

AU - Morita, Takashi

AU - Mori, Hiroshi

AU - Tomiyama, Takami

PY - 2017/7/31

Y1 - 2017/7/31

N2 - The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

AB - The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer's disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

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