- Open Access
Mutation-induced loss of APP function causes GABAergic depletion in recessive familial Alzheimer’s disease: analysis of Osaka mutation-knockin mice
- Tomohiro Umeda1, 2,
- Tetsuya Kimura3,
- Kayo Yoshida4,
- Keizo Takao5, 8,
- Yuki Fujita1,
- Shogo Matsuyama6,
- Ayumi Sakai1,
- Minato Yamashita1,
- Yuki Yamashita1,
- Kiyouhisa Ohnishi1,
- Mamiko Suzuki3,
- Hiroshi Takuma1,
- Tsuyoshi Miyakawa5,
- Akihiko Takashima3,
- Takashi Morita4,
- Hiroshi Mori2, 7 and
- Takami Tomiyama1, 2Email authorView ORCID ID profile
© The Author(s). 2017
- Received: 4 July 2017
- Accepted: 21 July 2017
- Published: 31 July 2017
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.
- Alzheimer’s disease
- Recessive mutation
- Knockin mouse
- Loss of function
Cerebral accumulation of Aβ oligomers is believed to be the initial step in the pathogenesis of Alzheimer’s disease (AD) [2, 29]. Aβ is generated from amyloid precursor protein (APP) by the function of two distinct enzymes, β- and γ-secretase . γ-Secretase is a complex composed of at least four membrane proteins in which presenilin 1 or presenilin 2 constitutes the catalytic subunits. Genetic studies have found that mutations in APP (chromosome 21), PSEN1 (chromosome 14), and PSEN2 (chromosome 1) are linked to familial AD .
The inheritance of pathogenic mutations can be defined into two types, dominant and recessive, according to the impact of the mutant allele on the phenotype . Dominant mutations cause disease even in heterozygotes by 1) gain-of-toxic-function of the gene product, 2) loss-of-function with dominant-negative effect, and 3) loss-of-function if 50% level of the normal gene product is not sufficient for normal gene function (haploinsufficiency). On the other hand, recessive mutations cause disease only in homozygotes primarily by loss-of-function: heterozygotes do not show pathogenic phenotypes, since the wild-type counterpart overcomes the deficiency of the mutant protein.
All pathogenic mutations in APP, PSEN1, and PSEN2 affect Aβ production and/or aggregation and most of them are dominant . Meanwhile, there are few recessive mutations reported. The E693Δ (Osaka) mutation in APP, which corresponds to E22Δ in Aβ, is the first recessive mutation identified in AD . So far, two pedigrees with this mutation have been identified in Japan: one is in Osaka [20, 25] and the other is in the Inland Sea of Japan . In both pedigrees, only homozygotes (2 members in Osaka and 3 members in the latter) suffer from dementia. However, it is unclear what kind of loss-of-function is induced in patients. Studies with synthetic peptides revealed that this mutation accelerates Aβ oligomerization, but never causes Aβ fibrillization. When injected into the cerebral ventricle of normal rats, the mutant Aβ peptides inhibited long-term potentiation (LTP) more potently than wild-type peptides . Furthermore, in APP transgenic mice harboring this mutation (referred to as APPOSK mice), the produced Aβ formed abundant oligomers and accumulated within neurons to cause synaptic and cognitive impairment without forming amyloid plaques . The enhanced Aβ oligomer formation and the lack of senile plaques have also been suggested in homozygous human patients, which were surmised from Western blot of CSF samples and brain amyloid imaging [11, 20, 25]. Such phenotypes appear to represent gain-of-toxic-function, but nevertheless they are seen only in homozygotes. The second recessive mutation is the A673V mutation in APP, which corresponds to A2V in Aβ . This mutation has been shown to increase Aβ production and accelerate Aβ fibrillization, but the mutant Aβ do not aggregate when co-incubated with wild-type Aβ. Furthermore, what kind of loss-of-function is induced by this mutation is also unclear. Interestingly, A673T mutation at the same position in APP shows protective effects against AD by reducing Aβ production and aggregation .
To investigate the genetic traits of recessive AD mutations more closely, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced knockin mice (referred to as OSK-KI mice) displayed Aβ pathologies only in homozygotes. We noticed that their memory impairment preceded Aβ accumulation and accompanied GABAergic depletion, which was presumably caused by the loss-of-function of APP. Thus, the present study provides new insights into the mechanism underlying the recessive heredity of the Osaka mutation.
Generation of OSK-KI mice
PCR primers used for targeting vector construction, probe preparation, and mouse genotyping
5'-CCGATGATGGCGCCTTTGTTCGAACCCACATC (ΔTTC) AGCAAAGAACACCTTCGAAAGGAAGCCG-3'
TV-Am-3' R (AatII)
Am-5' probe R
Mouse monoclonal antibodies to Aβ oligomers (11A1; IBL, Fujioka, Japan), the presynaptic marker synaptophysin (SVP-38; Sigma, St. Louis, MO), the astrocyte marker glial fibrillary acidic protein (GFAP) (Cappel, Aurora, OH), the mature neuron marker NeuN (Chemicon, Temecula, CA), and the GABAergic neuron marker parvalbumin (PARV-19; Sigma) were purchased. Rabbit polyclonal antibodies to the microglia marker Iba-1 (Wako, Osaka, Japan), GABA-synthetic enzyme glutamate decarboxylase (GAD) 65/67 (EMD Millipore, Temecula, CA), vesicular GABA transporter (VGAT) (Proteintech, Rosemont, IL), vesicular glutamate transporter (VGLUT) 1/2 (Abcam, Cambridge, MA) and actin (Sigma) were also purchased. Mouse monoclonal antibody to pSer396/Ser404-tau (PHF-1) was a kind gift from Dr. Peter Davies (Department of Pathology, Albert Einstein College of Medicine, Bronx, NY), and rabbit polyclonal antibodies to Aβ42 (Ter42), Aβ N-terminus (β001), and APP C-terminus (C40) were prepared in our laboratory.
Spatial reference memory of male mice was assessed in Osaka City University at 4, 6, and 8 months using the Morris water maze, as described previously . In addition, comprehensive behavioral test battery was performed in the National Institute for Physiological Sciences on 8-month-old male mice to study their sensorimotor functions, locomotor activity, social behavior, anxiety-like behavior, depression-like behavior, and learning/memory, as described previously .
Brain sections were prepared as described previously . Aβ accumulation (Ter42, β001 and 11A1), abnormal tau phosphorylation (PHF-1), synapse loss (synaptophysin), and glial activation (GFAP and Iba-1), were examined as described previously , where only for Aβ staining, sections were pretreated by boiling in 0.01 N HCl (pH 2) for 10 min to expose epitopes. Neuronal loss was assessed with anti-NeuN antibody with (entorhinal) or without (hippocampus) boiling sections in 10 mM citrate buffer (pH 6) for 30 min. GABAergic interneurons were stained with anti-parvalbumin antibody after sections were boiled in 10 mM citrate buffer (pH 6) for 30 min.
To determine the expression levels of APP, brain tissues were homogenized in 5 volumes of 50 mM Tris–HCl (pH 7.6), 150 mM NaCl (Tris-buffered saline, TBS) containing 1% Triton X-100 and protease inhibitor cocktail (P8340; Sigma). After agitation at 4 °C for 1 h, the homogenates were centrifuged at 1000 x g for 15 min at 4 °C to remove insoluble materials. The supernatants were subjected to Western blot with antibodies to APP C-terminus (C40) and actin. In different experiments, hippocampal tissues were dissected from mouse brains and homogenized in 4 volumes of TBS containing P8340. The levels of synaptophysin, GAD65/67, VGAT, VGLUT1/2, and actin were examined by Western blot with corresponding antibodies. Signals were visualized and quantified using an ImageQuant LAS 500 (GE Healthcare Bio-Sciences, Uppsala, Sweden). The remaining brain tissues, not including the cerebellum, were also homogenized in 4 volumes of TBS containing P8340 and separated into TBS-soluble and SDS-soluble fractions by 2-step ultracentrifugation, the latter of which were dialyzed against TBS, essentially as described previously . The levels of Aβ42 in each fraction were measured using the Sensolyte anti-mouse/rat β-amyloid (1–42) quantitative ELISA kit Colorimetric (Anaspec, Fremont, CA). Aβ oligomers and phosphorylated tau in the homogenates were measured by direct ELISA with 11A1 antibody and by using the Human Tau [pS396] ELISA kit (Invitrogen, Camarillo, CA), respectively, as described previously .
Synaptic plasticity was examined by electrophysiology using hippocampal slices, essentially as described previously . Transverse hippocampal slices (350 μm thick) were prepared in ice-cold artificial cerebrospinal fluid (aCSF; NaCl 124 mM, KCl 3 mM, NaHCO3 26 mM, NaH2PO4 1.25 mM, CaCl2 2 mM, MgSO4 1 mM, and D-glucose 10 mM) containing 1 mM kynurenic acid. Slices were allowed to recover in aCSF at room temperature for 1–2 h and then transferred to the recording chamber, in which they were perfused at a rate of 2 ml/min with aCSF at 32 °C. Electrical stimulation was applied onto the molecular layer of dentate gyrus using a bipolar tungsten electrode, and field excitatory postsynaptic potential (fEPSP) was recorded using a glass electrode in the same region at 200-μm distance from the stimulating electrode. Baseline stimulation was 15- to 20-μA constant current pulse, which induces fEPSP at a level 50% the maximum amplitude, 100-μsec pulse duration, and 30-s pulse interval. After baseline recording for 15 min, high-frequency stimulation (HFS; 3 trains of 100 Hz, 100 pulses, 120-s train interval) with an intensity 2-fold higher than that of baseline stimulation was delivered. The produced fEPSP was recorded for 60 min in the presence or absence of a GABAA receptor antagonist picrotoxin (Sigma) at 40 μM. fEPSP slopes were compared at 60 min.
Diazepam treatment to OSK-KI mice
Diazepam (Sigma), a positive allosteric modulator of GABAA receptor, was dissolved to 10 μg/ml in 0.5% low-viscosity carboxymethylcellulose (CMC; Sigma). Diazepam is usually prescribed to adult humans at 2 to 10 mg orally 2 to 4 times a day for anxiety and seizures (https://www.drugs.com/dosage/diazepam.html). Thus, its minimum daily dose for humans is 4 mg. Assuming that mean body weights of adult humans and mice are 60 kg and 30 g, respectively, the minimum daily dose for mice corresponds to 2 μg. Thus, 200 μl of diazepam (i.e. 2 μg) or CMC solution was orally administered using feeding needles to 6-month-old male homozygotes (n = 9–10 per group) 5 days a week (Monday through Friday) for 2 months. Age-matched male non-KI littermates (n = 10) administered CMC solution were used as controls. Spatial reference memory was examined at 8 months using the Morris water maze as described above. Daily oral administration of diazepam was continued during the behavioral test. After the behavioral tests, brain sections were prepared and Aβ oligomer accumulation (11A1), synapse loss (synaptophysin), and GABAergic neurons (parvalbumin) were examined by immunohistochemistry as described above.
Transfection and western blot of mouse Aβ oligomers
Human APP695 constructs with the Swedish (K670 N/M671 L, SW) and Osaka mutations were prepared as described previously , from which mouse APP695 constructs were produced by site-directed mutagenesis. HEK293 cells were transfected with human or mouse APPSW and APPSW/OSK constructs, as described previously . The Swedish mutation was introduced just to increase total Aβ production. Three days after transfection, the cells from 5 culture dishes (10 cm diameter) were combined into 1 tube and homogenized by sonication in 1 mL of 1% Triton X-100/TBS containing P8340. After agitation at 4 °C for 1 h, the cell homogenates were centrifuged at 1000 x g for 15 min at 4 °C to remove cell debris. Aliquots of the supernatants were subjected to Western blot to measure APP expression (C40) and actin. Aβ in the remaining supernatants were immunoprecipitated using anti-Aβ antibody β001 and subjected to Western blot with the same antibody, essentially as described previously . Signals were visualized and quantified using an ImageQuant LAS 500.
Comparisons of means between more than two groups were performed using the Bonferroni/Dunn test in immunohistochemical and biochemical analyses, and the comparison of fEPSP slopes at 60 min in electrophysiology was done using the Tukey-Kramer test. Data in behavioral tests were analyzed using ANOVA or repeated measures ANOVA followed by the Tukey-Kramer test. Differences with a p value of less than 0.05 were considered significant.
Generation of OSK-KI mice
Memory impairment in OSK-KI mice
Phenotypes of OSK-KI mice in comprehensive behavioral test battery
Light/dark transition test
Elevated plus maze
Social interaction test
Social interaction test
Startle Response/Prepulse inhibition
Porsolt forced swim
Immobility time (behavioral despair)
Eight-arm radial maze
T-maze forced alternation
Contextual fear memory
Immobility time (behavioral despair)
Social interaction test
(24-h homecage monitoring)
Aβ-related neuropathology in OSK-KI mice
These results indicate that the Osaka mutation causes Aβ-related neuropathology in a recessive hereditary manner. However, these phenotypes were recognized only from 8 months, suggesting that a certain unidentified mechanism other than Aβ accumulation underlies the memory disturbance observed in 4-month-old homozygotes.
Aberrant synaptic activity in OSK-KI mice
GABAergic neuron loss in OSK-KI mice
Effects of diazepam treatment on memory and Aβ pathology in OSK-KI mice
In the present study, we generated a new mouse model of AD by knocking-in the Osaka mutation into endogenous mouse APP. The produced OSK-KI mice successfully displayed memory impairment, Aβ oligomer accumulation, and subsequent Aβ-related pathology. Since the exact neuropathology in human patients with the Osaka mutation is not known, we cannot validate the phenotypes of OSK-KI mice at the moment. Nevertheless, it is important that the above phenotypes were seen only in homozygotes, reflecting the recessive heredity of the Osaka mutation that was originally observed in humans [11, 20, 25]. In general, recessive mutations cause disease primarily by loss-of-function of the gene product . The fact that the Osaka mutation is recessive implies that this mutation induces a loss-of-function of APP. Then, what kind of loss-of-function is induced by the Osaka mutation? A hint was found in the paper of Wang et al. , where they demonstrated using APP knockout mice that APP is highly expressed in GABAergic interneurons in the dentate gyrus and plays an important role in GABAergic synapse formation. This information led us to speculate that the Osaka mutation impairs the APP function necessary for the formation and maintenance of GABAergic synapses. If this were the case, homozygous OSK-KI mice would show deficient GABAergic transmission in the dentate gyrus, which presumably leads to abnormal synaptic activation and resultant memory impairment. Our data appear to support this theory: 4-month-old homozygotes displayed decreased levels of dentate GABAergic neurons, abnormal LTP induction, and impaired memory. This GABAergic depletion was not likely caused by Aβ oligomers, because Aβ accumulation was first detected at 8 months and because only GABAergic, but not glutamatergic, neurons were affected at 4 months. Furthermore, only dentate, but not entorhinal, GABAergic neurons were significantly decreased, despite that the both regions accumulated Aβ oligomers. We also showed that the memory impairment in homozygotes could be rescued by oral administration of diazepam, an allosteric modulator of GABAA receptor to promote GABA binding and thereby enhance GABAergic inhibitory input. This finding further supports our theory that GABAergic depletion is a cause of memory disturbance.
Regarding the recessive heredity of the Osaka mutation, some other possibilities are also considered. First, we cannot exclude the possibility that the recessive appearance of the Osaka mutation is due to its incomplete penetrance or variable expressivity. However, we have not observed such symptoms in our OSK-KI mice except for synapse loss in 24-month-old heterozygotes. Second, it may be that the presence of wild-type Aβ interferes with the oligomerization of mutant Aβ, like the aforementioned recessive APP mutation A673V . This is unlikely, however, because APPOSK mice that express both mutant and wild-type Aβ at similar levels showed Aβ oligomer accumulation . Third, whether Aβ oligomers accumulate in the brain may simply depend on the concentration of mutant Aβ. Homozygotes express a sufficient amount of mutant Aβ, whereas heterozygotes produce only a half amount that in homozygotes, not reaching pathogenic levels. We assume that even in homozygotes, the amount of mutant Aβ is insufficient and GABAergic depletion is necessary for Aβ oligomer accumulation, as described above.
GABAergic dysfunction may underlie the pathogenesis of AD, not only in the Osaka mutation but also in other familial and sporadic cases. For example, it has been reported that the levels of GABA are reduced in the posterior cingulated cortex of amnestic mild cognitive impairment independently of amyloid deposition  and in the parietal cortex of patients with AD . Neuronal hyperactivity has also been observed in the presymptomatic stages of both sporadic and familial AD . Furthermore, two major Aβ-degrading enzymes, endothelin-converting enzyme-2 and neprilysin, were shown to be enriched in GABAergic interneurons in the hippocampus and neocortex , implying that GABAergic neuron loss results in lowered degradation and subsequent accumulation of Aβ. In this regard, it is noteworthy that previous use of benzodiazepine has been shown to be associated with lower cortical Aβ levels in non-demented elderly control subjects . These findings collectively implicate that pharmacological treatments to compensate GABAergic deficiency might have therapeutic potential in early stages of AD .
In summary, we elucidated here that the Osaka mutation has dual effects: it causes a loss-of-function of APP and gain-of-toxic-function of Aβ, though the latter seems to come out only after the former causes GABAergic depletion. To our knowledge, the present OSK-KI mice is the first mouse model to replicate the hereditary form of recessive familial AD, though the phenotypes are not yet validated in human cases. Furthermore, the present study demonstrates for the first time that mutation-induced loss of APP function could be a cause of recessive hereditary dementia.
We thank Rie Teraoka, Naomi Sakama, Reina Fujita, Maiko Mori, and Taro Nishiyama for their technical assistance, and Peter Karagiannis for reading the manuscript.
This study was supported by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (no. 20023026, 21,390,271, 23,110,514, 25,290,018, 16 K15132); by the Grant-in-Aid for Scientific Research on Innovative Areas (Comprehensive Brain Science Network) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by the Grants-in-Aid for Comprehensive Research on Dementia from the Ministry of Health, Labour, and Welfare, Japan; and in part by the Alzheimer’s Association (IIRG-09-132,098).
Availability of data and materials
The data generated and/or analyzed during the comprehensive behavioral test battery are available in the Mouse Phenotype Database [http://www.mouse-phenotype.org/], while the other data are available from the corresponding author upon reasonable request. Inquiries about OSK-KI mice should be addressed to the corresponding author.
TT, HM, TMo, AT, and TMi contributed to the conception and design of the study. TU, TK, KY, KT, YF, SM, AS, MY, YY, KO, MS, HT, TMo, and TT performed experiments and analyzed data. TT drafted the manuscript and TU prepared main figures. All authors read and approved the final manuscript.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.
Consent for publication
Drs. Umeda, Yoshida, Morita, Mori, and Tomiyama have a Japanese patent (No. 2015–50,032) on the knockin mouse pending.
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