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1.
Nat Commun ; 12(1): 2311, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875655

RESUMO

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.


Assuntos
Doença de Alzheimer/genética , Córtex Cerebral/metabolismo , Perfilação da Expressão Gênica/métodos , Hipocampo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Autopsia , Córtex Cerebral/patologia , Feminino , Hipocampo/patologia , Humanos , Aprendizado de Máquina , Masculino , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Inibidor da Proteína C/genética , Inibidor da Proteína C/metabolismo , RNA-Seq/métodos , Proteínas tau/genética , Proteínas tau/metabolismo
2.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805772

RESUMO

Sulforaphane, a potent dietary bioactive agent obtainable from cruciferous vegetables, has been extensively studied for its effects in disease prevention and therapy. Sulforaphane potently induces transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated expression of detoxification, anti-oxidation, and immune system-modulating enzymes, and possibly acts as an anti-carcinogenic agent. Several clinical trials are in progress to study the effect of diverse types of cruciferous vegetables and sulforaphane on prostate cancer, breast cancer, lung cancer, atopic asthmatics, skin aging, dermatitis, obesity, etc. Recently, the protective effects of sulforaphane on brain health were also considerably studied, where the studies have further extended to several neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorder, and schizophrenia. Animal and cell studies that employ sulforaphane against memory impairment and AD-related pre-clinical biomarkers on amyloid-ß, tau, inflammation, oxidative stress, and neurodegeneration are summarized, and plausible neuroprotective mechanisms of sulforaphane to help prevent AD are discussed. The increase in pre-clinical evidences consistently suggests that sulforaphane has a multi-faceted neuroprotective effect on AD pathophysiology. The anti-AD-like evidence of sulforaphane seen in cells and animals indicates the need to pursue sulforaphane research for relevant biomarkers in AD pre-symptomatic populations.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Isotiocianatos/farmacologia , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Sulfóxidos/farmacologia , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Regulação da Expressão Gênica , Humanos , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Agregados Proteicos/genética , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
3.
Nat Commun ; 12(1): 1903, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771994

RESUMO

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer's disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD.


Assuntos
Doença de Alzheimer/genética , Proteínas do Citoesqueleto/genética , Transtornos da Memória/genética , MicroRNAs/genética , Sinapses/metabolismo , Quinases Associadas a rho/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/fisiologia , Fosforilação , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sinapses/fisiologia , Quinases Associadas a rho/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
4.
Neuron ; 109(8): 1283-1301.e6, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33675684

RESUMO

Loss-of-function TREM2 mutations strongly increase Alzheimer's disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of ß-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both ß-amyloid and tau pathologies, we examined Trem2 deficiency in the pR5-183 mouse model expressing mutant tau alone or in TauPS2APP mice, in which ß-amyloid pathology exacerbates tau pathology and neurodegeneration. Single-cell RNA sequencing in these models revealed robust disease-associated microglia (DAM) activation in TauPS2APP mice that was amyloid-dependent and Trem2-dependent. In the presence of ß-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without ß-amyloid pathology, Trem2 deletion did not affect these processes. Therefore, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which ß-amyloid facilitates the spreading of pathogenic tau.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Atrofia/genética , Atrofia/metabolismo , Atrofia/patologia , Encéfalo/patologia , Modelos Animais de Doenças , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Receptores Imunológicos/genética , Proteínas tau/genética
5.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760152

RESUMO

The aim of the present study was to investigate the neuroprotective effects of naringin on the memory impairment of hydrocortisone mice, and to elucidate the potential underlying molecular mechanisms. In the present study, a hydrocortisone model was constructed. Novel object recognition, Morris water maze and step­down tests were performed in order to assess the learning and memory abilities of mice. Hematoxylin and eosin staining was used to observe pathological changes in the hippocampus and hypothalamus. Transmission electron microscopy was used to observe the ultrastructural changes in the hippocampus. Immunohistochemistry was used to detect the expression of ERα and ERß. Western blotting was performed to detect the expression of each protein in the relevant system. It was found that naringin can significantly improve cognitive, learning and memory dysfunction in mice with hydrocortisone memory impairment. In addition, naringin can exert neuroprotective effects through a variety of mechanisms, including amyloid ß metabolism, Tau protein hyperphosphorylation, acetylcholinergic system, glutamate receptor system, oxidative stress and cell apoptosis. Naringin can also affect the expression of phosphorylated­P38/P38, indicating that the neuroprotective effect of naringin may also involve the MAPK/P38 pathway. The results of the present study concluded that naringin can effectively improve the cognitive abilities of mice with memory impairment and exert neuroprotective effects. Thus, naringin may be a promising target drug candidate for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Flavanonas/farmacologia , Transtornos da Memória/tratamento farmacológico , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/genética , Transtornos da Memória/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética
6.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652938

RESUMO

PET of ß-Amyloid plaques (Aß) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aß peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aß+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aß-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Fluordesoxiglucose F18/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/isolamento & purificação , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Demência/diagnóstico , Demência/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/genética , Proteínas tau/isolamento & purificação
7.
Science ; 371(6532)2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33632820

RESUMO

Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer's disease, other neurodegenerative conditions, autism, and epilepsy. Tau is abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological processes. Informative disease models have revealed a plethora of abnormal tau species and mechanisms that might contribute to neuronal dysfunction and loss, but the relative importance of their respective contributions is uncertain. This knowledge gap poses major obstacles to the development of truly impactful therapeutic strategies. The current expansion and intensification of efforts to translate mechanistic insights into tau-related therapeutics should address this issue and could deliver better treatments for a host of devastating conditions.


Assuntos
Encefalopatias/metabolismo , Encefalopatias/terapia , Tauopatias/metabolismo , Tauopatias/terapia , Proteínas tau/metabolismo , Animais , Encéfalo/fisiologia , Humanos , Microtúbulos/metabolismo , Neurônios/fisiologia , Proteínas tau/química , Proteínas tau/genética
8.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33604685

RESUMO

Yuan­zhi­san (YZS) is a classic type of Traditional Chinese Medicine, which has been reported to aid in the treatment of Alzheimer's disease (AD). The present study aimed to investigate the effects of YZS on tau protein aggregation, a hallmark of AD pathology, and its possible mechanisms. The results demonstrated that YZS improved learning and memory abilities, and decreased the severity of AD pathology in ß­amyloid (Aß1­40)­induced AD rats. Moreover, YZS administration inhibited the hyperphosphorylation of tau protein at Ser199 and Thr231 sites. Several vital enzymes in the ubiquitin­proteasome system (UPS), including ubiquitin­activating enzyme E1a/b, ubiquitin­conjugating enzyme E2a, carboxyl terminus of Hsc70­interacting protein, ubiquitin C­236 terminal hydrolase L1 and 26S proteasome, were all significantly downregulated in AD rats, which indicated an impaired enzymatic cascade in the UPS. In addition, it was identified that YZS treatment partly increased the expression levels of these enzymes in the brains of AD rats. In conclusion, the present results suggested that YZS could effectively suppress the hyperphosphorylation of tau proteins, which may be partially associated with its beneficial role in restoring functionality of the UPS.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/genética , Medicamentos de Ervas Chinesas/farmacologia , Fragmentos de Peptídeos/genética , Agregados Proteicos/efeitos dos fármacos , Proteínas tau/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Fosforilação/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/genética , Ratos , Ubiquitina/genética
9.
Neurology ; 96(13): e1743-e1754, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33597290

RESUMO

OBJECTIVE: To test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy, and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses. METHODS: A total of 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI and clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy, and performance across different cognitive domains were assessed. RESULTS: Total WMH volumes were larger in patients with bvFTD than patients with AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. Patients with bvFTD and patients with AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD. CONCLUSION: Increased WMH are common in patients with bvFTD and patients with AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Furthermore, increased WMH in different regions contributes to cognitive deficits.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Demência Frontotemporal/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Atrofia , Proteína C9orf72/genética , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tamanho do Órgão , Progranulinas/genética , Índice de Gravidade de Doença , Análise Espacial , Substância Branca/patologia , Proteínas tau/genética
10.
Neurosci Lett ; 750: 135764, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33621639

RESUMO

Alzheimer's disease (AD) is the main cause of dementia in the world. Studies of human AD brains show abnormalities in the white matter and reduction of myelin and oligodendrocyte markers. It has been proposed that oligodendrocyte progenitor cells (OPCs) present in the adult brain are a potential source for re-myelination, through proliferation and differentiation into mature oligodendrocytes. Bexarotene, a Retinoid X Receptor agonist, has been demonstrated to reverse behavioral deficits and to improved synaptic transmission and plasticity in murine models of AD, which was associated with the reduction of soluble Aß peptides. In the present study, we analyzed changes in the expression of oligodendrocyte lineage markers following oral administration of Bexarotene in a very old (24-month-old) triple transgenic mouse model of AD (3xTg-AD), for which early demyelination changes have been previously described. Bexarotene increased the expression of OPCs and intermediate oligodendrocyte progenitors (Olig2+ and O4+), and increased the number of mitotic (O4+) and myelinating mature (MBP+) oligodendrocytes. We clearly show that Bexarotene promotes re-myelination which might be important for the previously observed cognitive improvement of 3xTg-AD mice treated with this drug.


Assuntos
Doença de Alzheimer/metabolismo , Bexaroteno/farmacologia , Bainha de Mielina/metabolismo , Fármacos Neuroprotetores/farmacologia , Oligodendroglia/efeitos dos fármacos , Receptores X Retinoide/agonistas , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Proliferação de Células , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/metabolismo , Oligodendroglia/fisiologia , Presenilina-1/genética , Proteínas tau/genética
11.
Neurology ; 96(9): e1347-e1357, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33408147

RESUMO

OBJECTIVE: To understand the time course of ß-amyloid (Aß) deposition in the brain, which is crucial for planning therapeutic trials of Aß-lowering therapies in Alzheimer disease (AD). METHODS: Two samples of participants from the Alzheimer's Disease Neuroimaging Initiative were studied with [18F]Florbetapir (FBP) Aß PET and followed for up to 9 years. Sample A included 475 cognitively normal (CN) older people and those with mild cognitive impairment (MCI) and AD and sample B included 220 CN Aß- individuals. We examined the trajectory of FBP over time in sample A and the incidence rate of conversion from negative to positive Aß PET scans in sample B. RESULTS: The relationship between time and brain Aß was sigmoidal, taking 6.4 years to transition from amyloid negative to positive and another 13.9 years to the onset of MCI. Aß deposition rates began to slow only 3.8 years after reaching the positivity threshold. The incidence rate for scan positivity was 38/1,000 person-years, and factors associated with conversion were age, baseline FBP, and being a female APOE ε4 carrier. Among CN Aß- individuals, FBP slopes were associated with rates of memory decline and brain tau measured with [18F]Flortaucipir PET 5 years after baseline. CONCLUSIONS: Lowering brain Aß must be accomplished early in the evolution of AD. Transitions of PET scans from Aß- to Aß+ should be predictable, and it is reasonable to expect that lowering rates of Aß even in early stages could produce clinically significant benefits.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Compostos de Anilina , Apolipoproteína E4/genética , Carbolinas , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Etilenoglicóis , Feminino , Seguimentos , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Caracteres Sexuais , Proteínas tau/genética
12.
J Med Chem ; 64(3): 1497-1509, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33499592

RESUMO

For the first time, the in silico design, screening, and in vitro validation of potent GSK-3ß type-II inhibitors are presented. In the absence of crystallographic evidence for a DFG-out GSK-3ß activation loop conformation, computational models were designed using an adapted DOLPHIN approach and a method consisting of Prime loop refinement, induced-fit docking, and molecular dynamics. Virtual screening of the Biogenics subset from the ZINC database led to an initial selection of 20 Phase I compounds revealing two low micromolar inhibitors in an isolated enzyme assay. Twenty more analogues (Phase II compounds) related to the hit [pyrimidin-2-yl]amino-furo[3,2-b]furyl-urea scaffold were selected for structure-activity relationship analysis. The Phase II studies led to five highly potent nanomolar inhibitors, with compound 23 (IC50 =0.087 µM) > 100 times more potent than the best Phase I inhibitor, and selectivity for GSK-3ß inhibition compared to homologous kinases was observed. Ex vivo experiments (SH-SY5Y cell lines) for tau hyperphosphorylation revealed promising neuroprotective effects at low micromolar concentrations. The type-II inhibitor design has been unraveled as a potential route toward more clinically effective GSK-3ß inhibitors.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fosforilação , Relação Estrutura-Atividade , Especificidade por Substrato , Proteínas tau/biossíntese , Proteínas tau/genética
13.
Adv Exp Med Biol ; 1281: 77-92, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433870

RESUMO

Numerous kindreds with familial frontotemporal lobar degeneration have been linked to mutations in microtubule-associated protein tau (MAPT) or progranulin (GRN) genes. While there are many similarities in the clinical manifestations and associated neuroimaging findings, there are also distinct differences. In this review, we compare and contrast the demographic/inheritance characteristics, histopathology, pathophysiology, clinical aspects, and key neuroimaging findings between those with MAPT and GRN mutations.


Assuntos
Demência Frontotemporal , Degeneração Lobar Frontotemporal , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Degeneração Lobar Frontotemporal/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Neuroimagem , Progranulinas/genética , Proteínas tau/genética
14.
Adv Exp Med Biol ; 1281: 123-139, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433873

RESUMO

A timely diagnosis of frontotemporal degeneration (FTD) is frequently challenging due to the heterogeneous symptomatology and poor phenotype-pathological correlation. Fluid biomarkers that reflect FTD pathophysiology could be instrumental in both clinical practice and pharmaceutical trials. In recent years, significant progress has been made in developing biomarkers of neurodegenerative diseases: amyloid-ß and tau in cerebrospinal fluid (CSF) can be used to exclude Alzheimer's disease, while neurofilament light chain (NfL) is emerging as a promising, albeit nonspecific, marker of neurodegeneration in both CSF and blood. Gene-specific biomarkers such as PGRN in GRN mutation carriers and dipeptide repeat proteins in C9orf72 mutation carriers are potential target engagement markers in genetic FTD trials. Novel techniques capable of measuring very low concentrations of brain-derived proteins in peripheral fluids are facilitating studies of blood biomarkers as a minimally invasive alternative to CSF. A major remaining challenge is the identification of a biomarker that can be used to predict the neuropathological substrate in sporadic FTD patients.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Peptídeos beta-Amiloides , Biomarcadores , Proteína C9orf72 , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Humanos , Proteínas de Neurofilamentos , Proteínas tau/genética
15.
Adv Exp Med Biol ; 1281: 269-282, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433880

RESUMO

Frontotemporal dementia (FTD) is a neurodegenerative disease with high heritability. Almost half of all familial cases are caused by mutations in one of the three genes MAPT, GRN and C9orf72. Even though major advances in FTD research have been achieved during the last decades, it is not yet fully understood how mutations in these diverse genes lead to the disease. To improve our understanding of FTD, the Risk and Modifying Factors in Frontotemporal Dementia (RiMod-FTD) consortium has created an FTD-specific multi-omics data resource. Using multiple omics technologies on post-mortem brain tissue from patients with mutations in GRN, MAPT or C9orf72 and healthy controls, the resource aims to provide a comprehensive cellular profile of FTD. Furthermore, brain tissue from multiple mouse models and induced pluripotent stem cells (iPSC)-derived neuronal cultures were profiled with similar multi-omics technologies to make up for the shortcomings of post-mortem brain tissue. All data are publicly available to all researchers, and ongoing efforts aim to increase the available datasets and to improve their accessibility. The RiMod-FTD resource represents a uniquely valuable dataset for the field of FTD research, which we hope will accelerate the scientific progress in the field.


Assuntos
Demência Frontotemporal , Doenças Neurodegenerativas , Doença de Pick , Animais , Proteína C9orf72/genética , Demência Frontotemporal/genética , Humanos , Camundongos , Mutação , Proteínas tau/genética
16.
JAMA Netw Open ; 4(1): e2030194, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33404617

RESUMO

Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation. Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease course (51.7%-100% of patients). Patients with MAPT variants showed the highest frequency and severity of most behavioral symptoms, particularly disinhibition (79.3%-100% of patients) and compulsive behavior (64.3%-100% of patients), compared with C9orf72 carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) and GRN carriers (38.2%-100% with disinhibition and 20.6%-100% with compulsive behavior). Alongside behavioral symptoms, neuropsychiatric symptoms were very frequently reported in patients with genetic FTD: anxiety and depression were most common in GRN carriers (23.8%-100% of patients) and MAPT carriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common in C9orf72 carriers (10.3%-54.5% of patients). Most behavioral and neuropsychiatric symptoms increased in the early-intermediate phases and plateaued in the late stages of disease, except for depression, which steadily declined in C9orf72 carriers, and depression and anxiety, which surged only in the late stages in GRN carriers. Conclusions and Relevance: This cohort study suggests that behavioral and neuropsychiatric disturbances differ between the common FTD gene variants and have different trajectories throughout the course of disease. These findings have crucial implications for counseling patients and caregivers and for the design of disease-modifying treatment trials in genetic FTD.


Assuntos
Demência Frontotemporal , Idoso , Ansiedade , Apatia , Proteína C9orf72/genética , Canadá , Comportamento Compulsivo , Depressão , Progressão da Doença , Europa (Continente) , Feminino , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Granulinas/genética , Alucinações , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas tau/genética
17.
Adv Exp Med Biol ; 1281: 177-199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433876

RESUMO

Filamentous inclusions of tau protein are found in cases of inherited and sporadic frontotemporal dementias (FTDs). Mutations in MAPT, the tau gene, cause approximately 5% of cases of FTD. They proved that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. Clinically and pathologically, cases with MAPT mutations can resemble sporadic diseases, such as Pick's disease, globular glial tauopathy, progressive supranuclear palsy and corticobasal degeneration. The structures of tau filaments from Pick's disease and corticobasal degeneration, determined by electron cryo-microscopy, revealed the presence of specific tau folds in each disease, with no inter-individual variation. The same was true of chronic traumatic encephalopathy.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença de Pick , Tauopatias , Demência Frontotemporal/genética , Humanos , Tauopatias/genética , Proteínas tau/genética
18.
Adv Exp Med Biol ; 1281: 113-121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33433872

RESUMO

Around one-third of frontotemporal dementia (FTD) is autosomal dominant with the major genetic causes being mutations in MAPT, GRN and C9orf72. Studying familial forms of FTD can provide a window into the earliest stages of the illness, many years before symptoms start. Large cohort studies have been set up in recent years to better understand this presymptomatic phase, including the Genetic FTD Initiative (GENFI) and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (ARTFL/LEFFTDS) studies. Whilst these studies have focused on the investigation of a variety of aspects of genetic FTD, from understanding the molecular pathogenesis to developing biomarkers, they also have a common goal: finding a way to prevent FTD. Researchers from these cohort studies have therefore come together to form the FTD Prevention Initiative (FPI), which has the overarching aim of promoting clinical trials of new therapies to prevent FTD through creating an international database of participants eligible for trials and uniform standards for conducting such trials. This chapter outlines the work of the FPI so far and its future goals over the next few years.


Assuntos
Demência Frontotemporal , Doença de Pick , Proteína C9orf72/genética , Estudos de Coortes , Demência Frontotemporal/genética , Demência Frontotemporal/prevenção & controle , Humanos , Mutação , Proteínas tau/genética
19.
Gene ; 766: 145146, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32941952

RESUMO

The removal of introns from mRNA precursors (pre-mRNAs) is an essential step in eukaryotic gene expression. The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to altered cellular conditions. Hypoxia also plays a key role in the pathophysiology of many diseases, including Alzheimer's disease (AD). In the presented study, we have examined the influence of cellular hypoxia on mRNA splice variant formation from Alzheimer's disease-related Tau and APP genes in brain cells. We have shown that the hypoxic microenvironment influenced the formation of Tau mRNA splice variants, but had no effect on APP mRNA splice variant formation. Additionally, our presented results indicate that splicing factor SRSF1 but not SRSF5 alters the formation of Tau cellular mRNA splice variants in hypoxic cells. Obtained results have also shown that hypoxic brain cells possess enhanced CLK1-4 kinase mRNA levels. This study underlines that cellular hypoxia can influence disease development through changing pre-mRNA splicing.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Hipóxia Celular/genética , RNA Mensageiro/genética , Proteínas tau/genética , Processamento Alternativo/genética , Encéfalo/metabolismo , Linhagem Celular Tumoral , Humanos , Íntrons/genética , Precursores de RNA/genética , Transcrição Genética/genética
20.
Neuroscience ; 455: 195-211, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33346120

RESUMO

Synapse or dendritic spine loss is the strongest correlate of cognitive decline in Alzheimer's disease (AD), and neurofibrillary tangles (NFTs), but not amyloid-ß plaques, associate more closely with transition to mild cognitive impairment. Yet, how dendritic spine architecture is affected by hyperphosphorylated tau is still an ongoing question. To address this, we combined cell and biochemical analyses of the Tau P301S mouse line (PS19). Individual pyramidal neurons in the hippocampus and medial prefrontal cortex (mPFC) were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and 3D morphometry analysis. In the hippocampus, PS19 mice and non-transgenic (NTG) littermates displayed equivalent spine density at 6 and 9 months, but both genotypes exhibited age-related thin spine loss. PS19 mice exhibited significant increases in synaptic tau protein levels and mean dendritic spine head diameter with age. This suggests that CA1 pyramidal neurons in PS19 mice may undergo spine remodeling in response to tau accumulation and age. In the mPFC, spine density was similar among PS19 mice and NTG littermates at 6 and 9 months, but age-related reductions in synaptic tau levels were observed among PS19 mice. Collectively, these studies reveal brain region-specific changes in dendritic spine density and morphology in response to age and the presence of hyperphosphorylated tau in the PS19 mouse line.


Assuntos
Doença de Alzheimer , Espinhas Dendríticas , Tauopatias , Proteínas tau , Animais , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas tau/genética , Proteínas tau/metabolismo
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