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1.
J Neuroinflammation ; 16(1): 173, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470863

RESUMO

BACKGROUND: Disturbances in clock genes affect almost all patients with Alzheimer's disease (AD), as evidenced by their altered sleep/wake cycle, thermoregulation, and exacerbation of cognitive impairment. As microglia-mediated neuroinflammation proved to be a driver of AD rather than a result of the disease, in this study, we evaluated the relationship between clock gene disturbance and neuroinflammation in microglia and their contribution to the onset of AD. METHODS: In this study, the expression of clock genes and inflammatory-related genes was examined in MACS microglia isolated from 2-month-old amyloid precursor protein knock-in (APP-KI) and wild-type (WT) mice using cap analysis gene expression (CAGE) deep sequencing and RT-PCR. The effects of clock gene disturbance on neuroinflammation and relevant memory changes were examined in 2-month-old APP-KI and WT mice after injection with SR9009 (a synthetic agonist for REV-ERB). The microglia morphology was studied by staining, neuroinflammation was examined by Western blotting, and cognitive changes were examined by Y-maze and novel object recognition tests. RESULTS: CLOCK/BMAL1-driven transcriptional negative feedback loops were impaired in the microglia from 2-month-old APP-KI mice. Pro-inflammatory genes in microglia isolated from APP-KI mice were significantly higher than those isolated from WT mice at Zeitgeber time 14. The expression of pro-inflammatory genes was positively associated with NF-κB activation and negatively associated with the BMAL1 expression. SR9009 induced the activation of microglia, the increased expression of pro-inflammatory genes, and cognitive decline in 2-month-old APP-KI mice. CONCLUSION: Clock gene disturbance in microglia is involved in the early onset of AD through the induction of chronic neuroinflammation, which may be a new target for preventing or slowing AD.

2.
Nutrients ; 11(8)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426549

RESUMO

The biological effects of insulin signaling are regulated by the phosphorylation of insulin receptor substrate 1 (IRS1) at serine (Ser) residues. In the brain, phosphorylation of IRS1 at specific Ser sites increases in patients with Alzheimer's disease (AD) and its animal models. However, whether the activation of Ser sites on neural IRS1 is related to any type of memory decline remains unclear. Here, we show the modifications of IRS1 through its phosphorylation at etiology-specific Ser sites in various animal models of memory decline, such as diabetic, aged, and amyloid precursor protein (APP) knock-in NL-G-F (APPKINL-G-F) mice. Substantial phosphorylation of IRS1 at specific Ser sites occurs in type 2 diabetes- or age-related memory deficits independently of amyloid-ß (Aß). Furthermore, we present the first evidence that, in APPKINL-G-F mice showing Aß42 elevation, the increased phosphorylation of IRS1 at multiple Ser sites occurs without memory impairment. Our findings suggest that the phosphorylation of IRS1 at specific Ser sites is a potential marker of Aß-unrelated memory deficits caused by type 2 diabetes and aging; however, in Aß-related memory decline, the modifications of IRS1 may be a marker of early detection of Aß42 elevation prior to the onset of memory decline in AD.

3.
Nanomedicine (Lond) ; 14(18): 2409-2422, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31456488

RESUMO

Aim: To determine whether a p38 MAPK inhibitor incorporated into nanoemulsion-based chitosan nanocapsules can reduce the activity of this kinase in the brain through their nasal administration in mice. Materials & methods: We selected the p38 MAPK inhibitor PH797804, an ATP-competitive inhibitor of p38α encapsulated in nanoemulsion-based chitosan nanocapsules. Biological effect was evaluated in microglial and neuronal cells in vitro and in ex vivo and in vivo systems, in a mouse model of Alzheimer's disease. Results: Encapsulated inhibitor retains enzymatic inhibitory activity and tissue penetration capacity in vitro, ex vivo and in vivo. Conclusion: Nasal administration of chitosan nanocapsules can be an effective approach for brain-restricted reduction of p38 MAPK activity, thus reducing the side effects of systemic administration.

4.
Dis Model Mech ; 12(9)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31439589

RESUMO

We studied a new amyloid-beta precursor protein (App) knock-in mouse model of Alzheimer's disease (AppNL-G-F ), containing the Swedish KM670/671NL mutation, the Iberian I716F mutation and the Artic E693G mutation, which generates elevated levels of amyloid beta (Aß)40 and Aß42 without the confounds associated with APP overexpression. This enabled us to assess changes in anxiety-related and social behaviours, and neural alterations potentially underlying such changes, driven specifically by Aß accumulation. AppNL-G-F knock-in mice exhibited subtle deficits in tasks assessing social olfaction, but not in social motivation tasks. In anxiety-assessing tasks, AppNL-G-F knock-in mice exhibited: (1) increased thigmotaxis in the open field (OF), yet; (2) reduced closed-arm, and increased open-arm, time in the elevated plus maze (EPM). Their ostensibly anxiogenic OF profile, yet ostensibly anxiolytic EPM profile, could hint at altered cortical mechanisms affecting decision-making (e.g. 'disinhibition'), rather than simple core deficits in emotional motivation. Consistent with this possibility, alterations in microstructure, glutamatergic-dependent gamma oscillations and glutamatergic gene expression were all observed in the prefrontal cortex, but not the amygdala, of AppNL-G-F knock-in mice. Thus, insoluble Aß overexpression drives prefrontal cortical alterations, potentially underlying changes in social and anxiety-related behavioural tasks.This article has an associated First Person interview with the first author of the paper.

5.
J Biol Chem ; 294(34): 12754-12765, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31273083

RESUMO

In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular ß-amyloid (Aß) deposition precedes the aggregation of pathological intracellular tau (the product of the gene microtubule-associated protein tau (MAPT)). To our knowledge, current mouse models of tauopathy reconstitute tau pathology by overexpressing mutant human tau protein. Here, through a homologous recombination approach that replaced the entire murine Mapt gene with the human ortholog, we developed knock-in mice with humanized Mapt to create an in vivo platform for studying human tauopathy. Of note, the humanized Mapt expressed all six tau isoforms present in humans. We next cross-bred the MAPT knock-in mice with single amyloid precursor protein (App) knock-in mice to investigate the Aß-tau axis in AD etiology. The double-knock-in mice exhibited higher tau phosphorylation than did single MAPT knock-in mice but initially lacked apparent tauopathy and neurodegeneration, as observed in the single App knock-in mice. We further observed that tau humanization significantly accelerates cell-to-cell propagation of AD brain-derived pathological tau both in the absence and presence of Aß-amyloidosis. In the presence of Aß-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that Aß-amyloidosis affects tau pathology. Our results also indicated that the pathological human tau interacts better with human tau than with murine tau, suggesting species-specific differences between these orthologous pathogenic proteins. We propose that the MAPT knock-in mice will make it feasible to investigate the behaviors and characteristics of human tau in an animal model.

6.
Nat Commun ; 10(1): 2964, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263162

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

7.
Neurobiol Aging ; 81: 166-176, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31284126

RESUMO

The amyloid beta (Aß) peptide is associated with the neurodegenerative and inflammatory changes in brains affected by Alzheimer's disease (AD). We hypothesized that the enteric nervous system also produces Aß in an intestinal component of disease. To test this idea, we compared C57BL/6 wild-type (WT) male and female mice to two models of Alzheimer's disease, amyloid precursor protein (APP)/presenilin 1 (PS1) mice and amyloid precursor protein NL-G-F (AppNL-G-F) mice, at 3, 6, and 12 months of age. Brain Aß plaque deposition in AppNL-G-F mice preceded that in the APP/PS1 mice, observable by 3 months. Three-month-old female AppNL-G-F mice had decreased intestinal motility compared with WT and APP/PS1 mice. However, 3-month-old female APP/PS1 mice demonstrated increased intestinal permeability compared with WT and AppNL-G-F mice. Both sexes of APP/PS1 and AppNL-G-F mice demonstrated increased colon lipocalin 2 mRNA and insoluble Aß 1-42 levels at 3 months. These data demonstrate an unrecognized enteric aspect of disease in 2 different mouse models correlating with the earliest brain changes.

8.
J Nucl Med ; 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31302633

RESUMO

Aim: Non-physiological overexpression of ß-amyloid (Aß) precursor protein in common transgenic Aß mouse models of Alzheimer's disease (AD) likely hampers their translational potential. The novel AppNL-G-F mouse incorporates a mutated knock-in, potentially presenting an improved model of AD for Aß-targeting treatment trials. We aimed to establish serial small animal positron-emission-tomography (µPET) of amyloidosis and neuroinflammation in AppNL-G-F mice as a tool for therapy monitoring. Methods: AppNL-G-F mice (homozygous n = 20; heterozygous n = 21) and age-matched wild-type mice (n = 12) were investigated longitudinally from 2.5 to 10 months of age with 18F-florbetaben Aß-µPET and 18F-GE-180 18kDa translocator protein (TSPO)-µPET. Voxel-wise analysis of standardized-uptake-value-ratios (SUVR) images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final µPET scan. Quantification of fibrillar Aß and activated microglia by immunohistochemistry and biochemistry served for validation of µPET results. Results: The periaqueductal gray emerged as a suitable pseudo-reference tissue for both tracers. Homozygous AppNL-G-F mice had rising SUVR in cortex and hippocampus for Aß- (+9.1%, +3.8%) and TSPO- (+19.8%, +14.2%) µPET from 2.5 to 10 months of age (all P < 0.05), whereas heterozygous AppNL-G-F mice did not show significant changes with age. Significant voxel-wise clusters of Aß deposition and microglial activation in homozygous mice appeared at five months of age. Immunohistochemical and biochemical findings correlated strongly with µPET data. Water maze escape latency was significantly elevated in homozygous AppNL-G-F mice compared to wild-type at ten months of age and was associated with high TSPO binding. Conclusion: Longitudinal µPET in AppNL-G-F knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice, but is insensitive to minor changes in heterozygous animals. The combination of µPET with behavioral tasks in AppNL-G-F treatment trails is poised to provide important insights in preclinical drug development.

9.
Science ; 365(6450)2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31221773

RESUMO

Cerebral blood flow is reduced early in the onset of Alzheimer's disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. We used live and rapidly fixed biopsied human tissue to establish disease relevance, and rodent experiments to define mechanism. We found that in humans with cognitive decline, amyloid ß (Aß) constricts brain capillaries at pericyte locations. This was caused by Aß generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aß could potentially reduce energy lack and neurodegeneration in AD.

10.
Nat Commun ; 10(1): 2394, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160584

RESUMO

To understand the molecular processes that link Aß amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer's disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Agregação Patológica de Proteínas/metabolismo , Células Piramidais/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Atrofia , Caspase 3/metabolismo , Morte Celular , Cromatografia Líquida , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Hipocampo/patologia , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/patologia , Células Piramidais/patologia , Tauopatias , Proteínas tau/metabolismo
11.
Biochem Biophys Res Commun ; 515(3): 462-467, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31164199

RESUMO

Irie and colleagues identified a "toxic conformer", which possesses a turn structure at positions 22-23, among various conformations of Aß and have been reporting its potent oligomeric capacity and neurotoxicity. This toxic conformer was detected in the brains of AD patients and AD model mice (Tg2576 line), and passive immunization targeting this conformer ameliorated the cognitive dysfunction in an AD model. In this study, we developed a novel AD mouse model (AppNL-P-F/NL-P-F) with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Aß, a mimic of the toxic conformer, utilizing the knock-in technique that well recapitulates the Aß pathology of AD patients in mice and avoids the artificial phenotype observed in transgenic-type model mice. We confirmed that AppNL-P-F/NL-P-F mice produce Aß by ELISA and accumulate senile plaques by immunohistochemistry at eight months of age. In WB, we observed a potential trimer band and high molecular-weight oligomer bands without a monomeric band in the TBS-soluble fraction of AppNL-P-F/NL-P-F mice at six months of age. In the novel object recognition test, cognitive impairment was observed at six months of age in these mice. These findings suggest that the toxic conformer of Aß induces cognitive dysfunction mediated by its oligomer formation in this mouse brain. AppNL-P-F/NL-P-F mice may be a useful model for evaluating Aß oligomer-induced cognitive impairment in AD and will aid in exploring therapeutic targets for AD pathology.

12.
Sci Rep ; 9(1): 7508, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101881

RESUMO

Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence of Alzheimer's disease, as well as other neurodegenerative disorders. Using a newly developed, highly sensitive reporter cell model, consisting of Jurkat T cells stably overexpressing a reporter gene and a gene encoding TREM2DAP12 fusion protein, we show here that TREM2-dependent signal transduction in response to apoptotic Neuro2a cells is mediated by aminophospholipid ligands, phosphatidylserine and phosphatidylethanolamine, which are not exposed on the intact cell surface, but become exposed upon apoptosis. We also show that signal-transducing TREM2 ligands different from aminophospholipids, which appear to be derived from neurons, might be present in membrane fractions of mouse cerebral cortex. These results may suggest that TREM2 regulates microglial function by transducing intracellular signals from aminophospholipids on apoptotic cells, as well as unidentified ligands in the membranes of the cerebral cortex.

13.
Neurochem Int ; 129: 104470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31102607

RESUMO

Apathy is clinically defined as lack of motivation. Apathy is a frequent symptom in patients with Alzheimer's disease (AD). It is unclear whether amyloid ß (Aß) pathology is associated with apathy. To address this question, we employed the AppNL-G-F/NL-G-F mouse, an Aß deposition-bearing mouse without neurofibrillary tangles and neuronal cell death throughout the lifespan and used a progressive-ratio (PR) task to monitor instrumental motivation between the ages of 16 and 39 weeks. In the PR task, the number of lever presses to receive one reward increases and the number of active lever presses in the final trial a mouse completes represents a break point, which is an index of motivation. During the observation period, AppNL-G-F/NL-G-F mice overall did not show impaired motivation. However, AppNL-G-F/NL-G-F mice showed a dispersion of the break point at 39 weeks of age within the group. Therefore, we examined the association between the degree of the break point and Aß pathology; the number of cored amyloid plaques in the striatum was inversely correlated with the degree of motivation. Furthermore, we measured the dopamine transporter (DAT) levels in the subcortical tissues including the striatum using western blot analysis and showed that AppNL-G-F/NL-G-F mice have lower DAT levels than do C57BL/6J mice. Although we could not directly determine the effect of core amyloid plaques on the DAT, the results of this study suggest a pathway through which cored amyloid plaques damage the DAT and cause impaired motivation. These results will draw attention to cored amyloid plaques and will aid researchers searching for new strategies that are effective for the prevention and treatment of impaired motivation.

14.
Sci Adv ; 5(4): eaau8237, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30989111

RESUMO

Dysfunctional mTOR signaling is associated with the pathogenesis of neurodevelopmental and neuropsychiatric disorders. However, it is unclear what molecular mechanisms and pathogenic mediators are involved and whether mTOR-regulated autophagy continues to be crucial beyond neurodevelopment. Here, we selectively deleted Atg7 in forebrain GABAergic interneurons in adolescent mice and unexpectedly found that these mice showed a set of behavioral deficits similar to Atg7 deletion in forebrain excitatory neurons. By unbiased quantitative proteomic analysis, we identified γ-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2) to differentially form high-molecular weight species in autophagy-deficient brains. Further functional analyses revealed a novel pathogenic mechanism involving the p62-dependent sequestration of GABARAP family proteins, leading to the reduction of surface GABAA receptor levels. Our work demonstrates a novel physiological role for autophagy in regulating GABA signaling beyond postnatal neurodevelopment, providing a potential mechanism for the reduced inhibitory inputs observed in neurodevelopmental and neuropsychiatric disorders with mTOR hyperactivation.

15.
BMC Neurosci ; 20(1): 13, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894120

RESUMO

BACKGROUND: Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce Aß 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 Aß 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 Aß 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 Aß40 and Aß42 in their brains. CONCLUSIONS: Aß 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.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Gliose/metabolismo , Placa Amiloide/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Gliose/patologia , Gliose/psicologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/psicologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/patologia , Placa Amiloide/psicologia , Memória Espacial/fisiologia
16.
Biol Pharm Bull ; 42(3): 354-356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828067

RESUMO

Reelin is a secreted protein that antagonizes the deposition and toxicity of amyloid ß peptide (Aß). Therefore, augmentation of Reelin activity may ameliorate Alzheimer's disease (AD). We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS-3) cleaves and inactivates Reelin in the mouse brain. In the present study, we investigated the effect of reducing ADAMTS-3 on deposition of Aß by crossbreeding drug-inducible ADAMTS-3 conditional knock-out (cKO) mice with "next-generation" AD model mice. We found that reducing ADAMTS-3 inhibited deposition of Aß significantly in AppNL-F mice, which produce human wild-type Aß. On the other hand, reducing ADAMTS-3 had no effect in AppNL-G-F mice, which produce the Arctic mutant Aß (E22G) that forms protofibrils more efficiently than does wild-type Aß. Thus, the findings suggest that the administration of an inhibitor against ADAMTS-3 will prevent the progression of AD pathology caused by deposition of wild-type Aß.


Assuntos
Proteínas ADAMTS/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteínas ADAMTS/antagonistas & inibidores , Proteínas ADAMTS/genética , Doença de Alzheimer , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
17.
Cereb Cortex ; 29(4): 1834-1850, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30766992

RESUMO

Synaptic dysfunction is widely proposed as an initial insult leading to the neurodegeneration observed in Alzheimer's disease (AD). We hypothesize that the initial insult originates in the lateral entorhinal cortex (LEC) due to deficits in key interneuronal functions and synaptic signaling mechanisms, in particular, Wnt (Wingless/integrated). To investigate this hypothesis, we utilized the first knock-in mouse model of AD (AppNL-F/NL-F), expressing a mutant form of human amyloid-ß (Aß) precursor protein. This model shows an age-dependent accumulation of Aß, neuroinflammation, and neurodegeneration. Prior to the typical AD pathology, we showed a decrease in canonical Wnt signaling activity first affecting the LEC in combination with synaptic hyperexcitation and severely disrupted excitatory-inhibitory inputs onto principal cells. This synaptic imbalance was consistent with a reduction in the number of parvalbumin-containing (PV) interneurons, and a reduction in the somatic inhibitory axon terminals in the LEC compared with other cortical regions. However, targeting GABAA receptors on PV cells using allosteric modulators, diazepam, zolpidem, or a nonbenzodiazepine, L-838,417 (modulator of α2/3 subunit-containing GABAA receptors), restored the excitatory-inhibitory imbalance observed at principal cells in the LEC. These data support our hypothesis, providing a rationale for targeting the synaptic imbalance in the LEC for early stage therapeutic intervention to prevent neurodegeneration in AD.

19.
PLoS One ; 13(12): e0206986, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30571684

RESUMO

T-type calcium channels in the brain mediate the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel therapeutic candidate, SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a] pyridine]-2-ene-3-carboxylate), for Alzheimer's disease (AD). The cognitive improvement by SAK3 is closely associated with enhanced acetylcholine (ACh) release in the hippocampus. Since monoamines such as dopamine (DA), noradrenaline (NA), and serotonin (5-HT) are also involved in hippocampus-dependent learning and psychomotor behaviors in mice, we investigated the effects of SAK3 on these monoamine releases in the mouse brain. Oral administration of SAK3 (0.5 mg/kg, p.o.) significantly promoted DA and 5-HT releases in the naive mouse hippocampal CA1 region but not in the medial prefrontal cortex (mPFC), while SAK3 did not affect NA release in either brain region. The T-type calcium channel-specific inhibitor, NNC 55-0396 (1 µM) significantly antagonized SAK3-enhanced DA and 5-HT releases in the hippocampus. Interestingly, the α7 nicotinic ACh receptor (nAChR) antagonist, methyllycaconitine (1 nM) significantly inhibited DA release, and the α4 nAChR antagonist, dihydro-ß-erythroidine (100 µM) significantly blocked both DA and 5-HT releases following SAK3 (0.5 mg/kg, p.o.) administration in the hippocampus. SAK3 did not alter basal monoamine contents both in the mPFC and hippocampus. SAK3 (0.5 mg/kg, p.o.) administration also significantly elevated DA and 5-HT releases in the hippocampal CA1 region of amyloid-precursor protein (APP)NL-GF knock-in (KI) mice. Moreover, hippocampal DA and 5-HT contents were significantly decreased in APPNL-GF KI mice. Taken together, our data suggest that SAK3 promotes monoamine DA and 5-HT releases by enhancing the T-type calcium channel and nAChR in the mouse hippocampus.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Região CA1 Hipocampal/efeitos dos fármacos , Canais de Cálcio Tipo T/metabolismo , Dopamina/metabolismo , Técnicas de Introdução de Genes , Imidazóis/farmacologia , Serotonina/metabolismo , Compostos de Espiro/farmacologia , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Canais de Cálcio Tipo T/deficiência , Canais de Cálcio Tipo T/genética , Cognição/efeitos dos fármacos , Técnicas de Inativação de Genes , Masculino , Camundongos
20.
J Alzheimers Dis ; 66(2): 801-809, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30320577

RESUMO

Commonly used Alzheimer's disease mouse models are based on the ectopic overexpression of the human amyloid precursor protein (APP) gene, together with a mutant presenilin gene. Surprisingly, humanized APP knock-in mouse models carrying a single APP Swedish mutation (AppNL), failed to develop amyloid plaque aggregation or cognitive deficits. Here we characterized the effect of this mutation in more advanced ages. We show that 24-month-old AppNL/NL mice, despite presenting an age dependent increase in insoluble amyloid-ß oligomers in the prefrontal cortex, they do not develop amyloid plaque deposition, reactive gliosis, or cognitive deficits.

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