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1.
Cells ; 10(11)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34831483

RESUMO

Alzheimer's disease (AD), the most common form of dementia, is characterized by amyloid-ß (Aß) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-ß deposition, synaptic dysfunction, neuroinflammation, and dysregulation of ß-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

2.
Mol Psychiatry ; 2021 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-34737456

RESUMO

Alzheimer's disease (AD) is characterized by the deposition of amyloid ß peptide (Aß) in the brain. The neuropeptide somatostatin (SST) regulates Aß catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here, we identified α-endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (KATP) channel, as a negative regulator of NEP downstream of SST signaling. The expression of ENSA is significantly increased in AD mouse models and in patients with AD. In addition, NEP directly contributes to the degradation of ENSA, suggesting a substrate-dependent feedback loop regulating NEP activity. We also discovered the specific KATP channel subtype that modulates NEP activity, resulting in the Aß levels altered in the brain. Pharmacological intervention targeting the particular KATP channel attenuated Aß deposition, with impaired memory function rescued via the NEP activation in our AD mouse model. Our findings provide a mechanism explaining the molecular link between KATP channel and NEP activation, and give new insights into alternative strategies to prevent AD.

3.
Elife ; 102021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609281

RESUMO

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for activated CD11c+ microglia and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimer's disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow (BM) cells to the pool of fetal-derived brain macrophages during the development of AD. We demonstrated that microglia remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor is replenished by, BM-derived cells. At the border-associated brain regions, bona fide CD206+ BAMs are minimally replaced by BM-derived cells, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by BM progenitors. This information further elucidates the turnover kinetics of these cells not only at steady state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.


Assuntos
Doença de Alzheimer/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Lectinas de Ligação a Manose/metabolismo , Microglia/metabolismo , Receptores de Superfície Celular/metabolismo , Doença de Alzheimer/embriologia , Animais , Modelos Animais de Doenças , Camundongos
4.
Elife ; 102021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34617884

RESUMO

Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer's disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis, and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of EEs caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4-induced endolysosomal trafficking defect and reduces plaque load.


Assuntos
Apolipoproteína E4/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Placa Amiloide/genética , Trocadores de Sódio-Hidrogênio/genética , Animais , Apolipoproteína E4/metabolismo , Feminino , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos , Camundongos Knockout , Trocadores de Sódio-Hidrogênio/metabolismo
5.
Genome Med ; 13(1): 168, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702310

RESUMO

BACKGROUND: In spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., ß-secretase) has proven to be insufficient to significantly alter the physiopathology of the disease, and we should therefore move from gene-centric to systemic therapeutic strategies, where AD-related changes are modulated globally. METHODS: Here we present the complete characterization of three murine models of AD at different stages of the disease (i.e., onset, progression and advanced). We combined the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Additionally, we derived specific Aß-related molecular AD signatures and looked for drugs able to globally revert them. RESULTS: We found that AD models show accelerated aging and that factors specifically associated with Aß pathology are involved. We discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable, and showed that at least two of them (i.e., lfit3 and Syt11) co-localize with Aß plaques in the brain. Finally, we found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aß plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels. CONCLUSIONS: The characterization of three AD mouse models at different disease stages provides an unprecedented view of AD pathology and how this differs from physiological aging. Moreover, our computational strategy to chemically revert AD signatures has shown that NSAID and anti-hypertensive drugs may still have an opportunity as anti-AD agents, challenging previous reports.

6.
Metabolites ; 11(9)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34564432

RESUMO

Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer's disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed by ultra-performance liquid chromatography followed by mass spectrometry. We found that a unique mannosylated-glycan is carried by a Tf isoform in CSF (Man-Tf). The cerebral cortex contained Man-Tf as a major isofom, suggesting that CSF Man-Tf is, at least partly, derived from the cortex. Man-Tf levels were analyzed in CSF of patients with neurological diseases. Concentrations of Man-Tf were significantly increased in AD and mild cognitive impairment (MCI) comparing with other neurological diseases, and the levels correlated well with those of phosphorylated-tau (p-tau), a representative AD marker. Consistent with the observation, p-tau and Tf were co-expressed in hippocampal neurons of AD, leading to the notion that a combined p-tau and Man-Tf measure could be a biomarker for AD. Indeed, levels of p-tau x Man-Tf showed high diagnostic accuracy for MCI and AD; 84% sensitivities and 90% specificities for MCI and 94% sensitivities and 89% specificities for AD. Thus Man-Tf could be a new biomarker for AD.

7.
Cell Death Dis ; 12(8): 769, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349120

RESUMO

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Increased Aß production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aß generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.

8.
J Neurochem ; 159(3): 603-617, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379812

RESUMO

Two common conjugated linoleic acids (LAs), cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid-ß (Aß) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of Aß in mouse neurons. CLA treatment did not affect the level of ß-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment, or Aß protein precursor (APP) in cultured neurons. BACE1 and γ-secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA-containing phosphatidylcholine (CLA-PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane-associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent Aß generation. Our findings suggest that the accumulation of c9,t11 CLA-PC/LPC in neuronal membranes suppresses the production of neurotoxic Aß in neurons.


Assuntos
Peptídeos beta-Amiloides/biossíntese , Ácido Linoleico/farmacologia , Ácidos Linoleicos Conjugados/farmacologia , Neurônios/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Suplementos Nutricionais , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Fosfatidilcolinas/metabolismo
9.
Mol Neurodegener ; 16(1): 47, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266459

RESUMO

BACKGROUND: Microglia are active modulators of Alzheimer's disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. METHODS: AppNL-F and AppNL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer's disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. RESULTS: Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in AppNL-F mice but was not evident in AppNL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. CONCLUSIONS: Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer's disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer's disease.

10.
Mol Neurodegener ; 16(1): 45, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215298

RESUMO

Neuritic plaques in Alzheimer's disease (AD) brains refer to ß-amyloid (Aß) plaques surrounded by dystrophic neurites (DNs), activated microglia and reactive astrocytes. Most recently, we showed that DNs form sequentially in three layers during plaque growth. Although lysosomal proteins such as LAMP1 are found in DNs, it is not clear how many and how early lysosomal proteins are involved in forming neuritic plaques. To answer this unmet question, we examined APP knock-in (APPNL-G-F), 5xFAD and APP/PS1ΔE9 mouse brains and found that the lysosomal activator proteins saposins (SAPs) and LAMP1 were accumulated to surround Aß plaques at the earliest stage, namely the 1st layer of DNs. Noticeably, lysosomal hydrolases were not detectable in these early DNs, suggesting that DNs at this early stage likely enrich dysfunctional lysosomes. In old AD mouse brains and in the later stage of human AD brains, SAP-C+-DNs and LAMP1+-DNs were gradually reduced in concomitant with the growth of amyloid plaques. Remarkably, the observed LAMP1 immunoreactivity near plaques in aged AD mouse and human brains were actually associated with disease-associated microglia rather than neuronal sources, likely reflecting more severely impaired lysosomal functions in neurons. Western blot analyses showed increased levels of SAP-C in AD mouse brains, and Aß oligomers induced elevated levels of SAP-C in cellular assays. The elevated protein levels of SAP-C in AD mouse brains during plaque growth potentially contributed lysosomal membrane leakage and loss of hydrolases. Together, our study indicates that lysosomal functions are impaired by being entrapped in DNs early during plaque growth, and this may viciously facilitate growth of amyloid plaques.

11.
Aging Cell ; 20(8): e13429, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34245097

RESUMO

Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock-in mouse model, AppNL-F/NL-F , which accumulates Aß plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6-month-old male AppNL-F/NL-F and wild-type mice were fed a regular or high-fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild-type and AppNL-F/NL-F mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aß deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD-fed AppNL-F/NL-F mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8-oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aß binding protein transthyretin (TTR) in AppNL-F/NL-F mice, suggesting that the depletion of TTR underlies the increased Aß deposition in the hippocampus of HFD-fed AppNL-F/NL-F mice.

12.
J Biol Chem ; 297(3): 101004, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34329683

RESUMO

We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice, respectively). These models showed Aß pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aß metabolism and clearance because the Arctic mutation renders Aß resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aß antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aß by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new third-generation mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças , Placa Amiloide/patologia , Animais , Técnicas de Introdução de Genes , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Placa Amiloide/genética , Presenilina-1/genética
13.
J Alzheimers Dis ; 82(4): 1513-1530, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34180416

RESUMO

BACKGROUND: The locus coeruleus (LC), a brainstem nucleus comprising noradrenergic neurons, is one of the earliest regions affected by Alzheimer's disease (AD). Amyloid-ß (Aß) pathology in the cortex in AD is thought to exacerbate the age-related loss of LC neurons, which may lead to cortical tau pathology. However, mechanisms underlying LC neurodegeneration remain elusive. OBJECTIVE: Here, we aimed to examine how noradrenergic neurons are affected by cortical Aß pathology in AppNL-G-F/NL-G-F knock-in mice. METHODS: The density of noradrenergic axons in LC-innervated regions and the LC neuron number were analyzed by an immunohistochemical method. To explore the potential mechanisms for LC degeneration, we also examined the occurrence of tau pathology in LC neurons, the association of reactive gliosis with LC neurons, and impaired trophic support in the brains of AppNL-G-F/NL-G-F mice. RESULTS: We observed a significant reduction in the density of noradrenergic axons from the LC in aged AppNL-G-F/NL-G-F mice without neuron loss or tau pathology, which was not limited to areas near Aß plaques. However, none of the factors known to be related to the maintenance of LC neurons (i.e., somatostatin/somatostatin receptor 2, brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) were significantly reduced in AppNL-G-F/NL-G-F mice. CONCLUSION: This study demonstrates that cortical Aß pathology induces noradrenergic neurodegeneration, and further elucidation of the underlying mechanisms will reveal effective therapeutics to halt AD progression.


Assuntos
Neurônios Adrenérgicos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/metabolismo , Locus Cerúleo/patologia , Degeneração Neural/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos , Camundongos Transgênicos
14.
J Nucl Med ; 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34088777

RESUMO

Positron emission tomography (PET) imaging of amyloid-ß (Aß) has become an important component of Alzheimer's disease (AD) diagnosis. 11C-Pittsburgh compound B (11C-PiB) and analogs bind to fibrillar Aß. However, levels of nonfibrillar, soluble aggregates of Aß, appear more dynamic during disease progression and more affected by Aß reducing treatments. The aim of this study was to compare an antibody-based PET ligand, targeting nonfibrillar Aß, with 11C-PiB after ß-secretase (BACE-1) inhibition in two AD mouse models at an advanced stage of Aß pathology. Methods: Transgenic ArcSwe mice (16 months) were treated with the BACE-1 inhibitor NB-360 for 2 months, while another group was kept as controls. A third group was analyzed at the age of 16 months as baseline. Mice were PET scanned with 11C-PiB to measure Aß plaque load followed by a scan with the bispecific radioligand 124I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Aß. The same study design was then applied for another mouse model, AppNL-G-F. In this case, NB-360 treatment was initiated at the age of 8 months and animals were scanned with 11C-PiB-PET and 125I-RmAb158-scFv8D3 single-photon emission computer tomography (SPECT). Brain tissue was isolated after scanning and Aß levels were assessed. Results: 124I-RmAb158-scFv8D3 concentrations measured with PET in hippocampus and thalamus of NB-360 treated ArcSwe mice were similar to those observed in baseline animals and significantly lower than concentrations observed in same-age untreated controls. Reduced 125I-RmAb158-scFv8D3 retention was also observed with SPECT in hippocampus, cortex and cerebellum of NB-360 treated AppNL-G-F mice. Radioligand in vivo concentrations corresponded with postmortem brain tissue analysis of soluble Aß aggregates. For both models, mice treated with NB-360 did not display a reduced 11C-PiB signal compared to untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11C-PiB signal than the baseline groups. Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aß levels after anti-Aß therapy in ArcSwe and AppNL-G-F mice with pronounced Aß pathology. In contrast, the decreased Aß levels could not be quantified with 11C-PiB PET, suggesting that these ligands detect different pools of the Aß.

15.
Pathol Res Pract ; 223: 153465, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33989885

RESUMO

We demonstrate that the introduction of GLI1 is sufficient for immortalized human astrocytes to be transformed whereas FOXM1 fails to induce malignant transformation, suggesting differences between GLI1 and FOXM1 in terms of transforming ability despite both transcription factors being overexpressed in malignant gliomas. Moreover, in investigations of mechanisms underlying relatively less-malignant features of GLI1-transformed astrocytes, we found that p27KIP1-positive cells were frequently observed in xenografts derived from GLI1-transformed astrocytes compared to those from RAS-transformed cells. As shRNA-mediated knockdown of p27KIP1 accelerates tumor progression of GLI1-transformed astrocytes, downregulation of p27KIP1 contributes to malignant features of transformed astrocytes. We propose that the models using immortalized/transformed astrocytes are useful to identify the minimal and most crucial set of changes required for glioma formation.

16.
J Neurosci ; 41(24): 5315-5329, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33980545

RESUMO

Impairment of episodic memory, a class of memory for spatiotemporal context of an event, is an early symptom of Alzheimer's disease. Both spatial and temporal information are encoded and represented in the hippocampal neurons, but how these representations are impaired under amyloid ß (Aß) pathology remains elusive. We performed chronic imaging of the hippocampus in awake male amyloid precursor protein (App) knock-in mice behaving in a virtual reality environment to simultaneously monitor spatiotemporal representations and the progression of Aß depositions. We found that temporal representation is preserved, whereas spatial representation is significantly impaired in the App knock-in mice. This is because of the overall reduction of active place cells, but not time cells, and compensatory hyperactivation of remaining place cells near Aß aggregates. These results indicate the differential impact of Aß aggregates on two major modalities of episodic memory, suggesting different mechanisms for forming and maintaining these two representations in the hippocampus.


Assuntos
Doença de Alzheimer/patologia , Região CA1 Hipocampal/patologia , Transtornos da Memória/patologia , Neurônios/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/toxicidade , Animais , Modelos Animais de Doenças , Masculino , Memória Episódica , Camundongos
17.
Sci Rep ; 11(1): 7289, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790404

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from AppNL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aß accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aß accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.


Assuntos
Doença de Alzheimer/metabolismo , Calmodulina/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Substituição de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Animais , Cálcio/metabolismo , Calmodulina/genética , Células Cultivadas , Dantroleno/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ligação Proteica , Proteínas tau/metabolismo
20.
J Alzheimers Dis ; 80(4): 1687-1704, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33720883

RESUMO

BACKGROUND: Epidemiological studies have shown that tooth loss is associated with Alzheimer's disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. OBJECTIVE: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. METHODS: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-ß (Aß) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aß ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. RESULTS: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. CONCLUSION: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Gliose/metabolismo , Transtornos da Memória/metabolismo , Placa Amiloide/metabolismo , Perda de Dente/complicações , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Gliose/patologia , Gliose/psicologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Transtornos da Memória/patologia , Transtornos da Memória/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/patologia , Placa Amiloide/psicologia , Perda de Dente/patologia
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