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1.
Nat Commun ; 12(1): 5261, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489404

RESUMO

The advent of single-cell RNA sequencing (scRNA-seq) technologies has revolutionized transcriptomic studies. However, large-scale integrative analysis of scRNA-seq data remains a challenge largely due to unwanted batch effects and the limited transferabilty, interpretability, and scalability of the existing computational methods. We present single-cell Embedded Topic Model (scETM). Our key contribution is the utilization of a transferable neural-network-based encoder while having an interpretable linear decoder via a matrix tri-factorization. In particular, scETM simultaneously learns an encoder network to infer cell type mixture and a set of highly interpretable gene embeddings, topic embeddings, and batch-effect linear intercepts from multiple scRNA-seq datasets. scETM is scalable to over 106 cells and confers remarkable cross-tissue and cross-species zero-shot transfer-learning performance. Using gene set enrichment analysis, we find that scETM-learned topics are enriched in biologically meaningful and disease-related pathways. Lastly, scETM enables the incorporation of known gene sets into the gene embeddings, thereby directly learning the associations between pathways and topics via the topic embeddings.


Assuntos
Bases de Dados Genéticas , Modelos Genéticos , Análise de Sequência de RNA/estatística & dados numéricos , Análise de Célula Única/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/estatística & dados numéricos , Genes Mitocondriais , Humanos , Camundongos , Redes Neurais de Computação , RNA Citoplasmático Pequeno , Retina/citologia , Retina/fisiologia , Análise de Sequência de RNA/métodos
2.
Zhen Ci Yan Jiu ; 46(8): 635-41, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472747

RESUMO

OBJECTIVE: To observe the effect of Sanjiao acupuncture(triple energizer acupuncture)on the small G protein guanosine triphosphate enzyme subfamily protein RhoA/Rho kinase (ROCK) pathway in Alzheimer's disease mice, and explore its effect on learning and memory function and neurosynaptic plasticity. METHODS: Forty SAMP8 senile dementia mice were randomly divided into model, Sanjiao acupuncture (acupuncture), non acupoint acupuncture (non-acupoint) and fasudil groups, with 10 mice in each group, another 10 SAMR normal aging mice were selected as normal aging group. Mice in the acupuncture group were treated with acupuncture intervention on "Danzhong"(CV18), "Zhongwan"(CV13), "Qihai"(BL24) and bilateral "Xuehai"(SP10) and "Zusanli" (ST36). Mice in the non-acupoint group were treated with acupuncture at each of the left and right non-acupoints under the ribs and mice in the fasudil group were intraperitoneally injected with fasudil (25 mg/kg). The mice in each group were given medicine or acupuncture on the second day after grouping for 28 continuously days, once a day. Morris water maze test was used to test the learning and memory ability of mice. HE staining was used to observe the pathological changes of neurons in hippocampus. The number of hippocampal neuron dendritic spine was detected by FD fast Golgi staining kit. The contents of ß-amyloid 42 (Aß42) and phosphorylated tau protein (p-tau) in hippocampus were detected by ELISA. Western blot was used to detect the protein relative expression levels of RhoA, ROCK, F-actin and p-cofilin in hippocampus. RESULTS: Compared with those in the normal aging group, the hippocampal neurons of the model group were disorderly arranged, the number of neuron was reduced, the escape latency, hippocampal Aß42 and p-tau contents, RhoA and ROCK protein expressions increased (P<0.05), the number of crossing the original platform, the number of neuronal dendritic spines, expressions of F-actin and p-cofilin decreased (P<0.05). After the interventions, there was no statistically significant difference in the above indicators in the non-acupoint group relevant to the model group (P>0.05). The acupuncture group and fasudil group improved the hippocampal pathological damage. The escape latency, hippocampal Aß42 and p-tau contents, the expressions of RhoA and ROCK protein decreased (P<0.05), and the number of crossing the original platform, the number of hippocampal neuron dendritic spines, expressions of F-actin and p-cofilin increased (P<0.05) in both of the acupuncture and fasudil groups in contrast to the model and non-acupoint groups. Compared with the acupuncture group, there was no significant difference in the above indicators in the fasudil group (P>0.05). CONCLUSION: Sanjiao acupuncture may inhibit the activation of the RhoA/ROCK pathway, so as to improve the learning and memory function of AD mice, increase the number of hippocampal neuron dendritic spines, and promote synaptic plasticity.


Assuntos
Terapia por Acupuntura , Doença de Alzheimer , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Aprendizagem , Camundongos , Plasticidade Neuronal , Quinases Associadas a rho/genética
3.
Zhongguo Zhong Yao Za Zhi ; 46(12): 3052-3057, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34467695

RESUMO

To study the material basis and mechanism of volatile oil from Alpinia oxyphylla in treating Alzheimer's disease(AD) based on GC-MS and network pharmacology. Ingredients of volatile oil from A.oxyphylla were analyzed by GC-MS. Targets of those ingredients were obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Relevant targets of AD were obtained through such databases as DrugBank, STITCH, OMIM. Intersection targets of ingredients and diseases were obtained by Online Venny map, and PPI network was established by STRING to screen out core targets. Gene ontology(GO) functional enrichment analysis and KEGG pathway enrichment analysis were performed by DAVID. The "ingredients-target-pathway" network was constructed by software Cytoscape 3.8.1 to screen out potential active ingredients of volatile oil from A.oxyphylla in the treatment of AD. The results showed that a total of 6 active ingredients were screened from the volatile oil of A.oxyphylla by GC-MS, 17 targets corresponding to 6 active ingredients were found in TCMSP database, and 3 448 AD targets were found in DrugBank database. "Ingredients-target-pathway" network and PPI network showed there were 4 potential active ingredients in the treatment of AD and 4 core targets. GO analysis and KEGG analysis showed 34(P<0.05) and 5(P<0.05) pathways, respectively, including nerve ligand receptor interaction, calcium signaling pathway, cholinergic synapse and 5-hydroxytryptaminergic synapse. This suggested that volatile oil from A.oxyphylla could synergistically treat AD by regulating calcium balance, cholinergic balance and phosphorylation. This study provided reference and guidance for further study of volatile oil from A.oxyphylla in the treatment of AD.


Assuntos
Alpinia , Doença de Alzheimer , Medicamentos de Ervas Chinesas , Óleos Voláteis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Simulação de Acoplamento Molecular
4.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360676

RESUMO

A growing body of evidence currently proposes that deep learning approaches can serve as an essential cornerstone for the diagnosis and prediction of Alzheimer's disease (AD). In light of the latest advancements in neuroimaging and genomics, numerous deep learning models are being exploited to distinguish AD from normal controls and/or to distinguish AD from mild cognitive impairment in recent research studies. In this review, we focus on the latest developments for AD prediction using deep learning techniques in cooperation with the principles of neuroimaging and genomics. First, we narrate various investigations that make use of deep learning algorithms to establish AD prediction using genomics or neuroimaging data. Particularly, we delineate relevant integrative neuroimaging genomics investigations that leverage deep learning methods to forecast AD on the basis of incorporating both neuroimaging and genomics data. Moreover, we outline the limitations as regards to the recent AD investigations of deep learning with neuroimaging and genomics. Finally, we depict a discussion of challenges and directions for future research. The main novelty of this work is that we summarize the major points of these investigations and scrutinize the similarities and differences among these investigations.


Assuntos
Doença de Alzheimer/diagnóstico , Encéfalo/diagnóstico por imagem , Aprendizado Profundo , Genômica/métodos , Neuroimagem/métodos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Humanos
5.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445402

RESUMO

Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and is notably dependent on age. One important inflammatory pathway exerted by innate immune cells of the nervous system in response to danger signals is mediated by inflammasomes (IF) and leads to the generation of potent pro-inflammatory cytokines. The protein "apoptosis-associated speck-like protein containing a caspase recruitment domain" (ASC) modulates IF activation but has also other functions which are crucial in AD. We intended to characterize immunohistochemically ASC and pattern recognition receptors (PRR) of IF in the hippocampus (HP) of the transgenic mouse model Tg2576 (APP), in which amyloid-beta (Aß) pathology is directly dependent on age. We show in old-aged APP a significant amount of ASC in microglia and astrocytes associated withAß plaques, in the absence of PRR described by others in glial cells. In addition, APP developed foci with clusters of extracellular ASC granules not spatiallyrelated to Aß plaques, which density correlated with the advanced age of mice and AD development. Clusters were associated withspecific astrocytes characterized by their enlarged ring-shaped process terminals, ASC content, and frequent perivascular location. Their possible implication in ASC clearance and propagation of inflammation is discussed.


Assuntos
Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Hipocampo/metabolismo , Doença de Alzheimer/genética , Animais , Grânulos Citoplasmáticos/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Transgênicos
6.
Biomolecules ; 11(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356626

RESUMO

Neurodegenerative disorders affect fifteen percent of the world's population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer's disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.


Assuntos
Doença de Alzheimer/metabolismo , Relógios Circadianos , Disfunção Cognitiva/metabolismo , Regulação da Expressão Gênica , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
7.
Biomolecules ; 11(7)2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34356628

RESUMO

Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. Various pathogenic mechanisms have been proposed to contribute to disease progression, and recent research provided evidence linking dysregulated circadian rhythms/sleep and energy metabolism with AD. Previously, we found that the natural compound Nobiletin (NOB) can directly activate circadian cellular oscillators to promote metabolic health in disease models and healthy aging in naturally aged mice. In the current study, using the amyloid-ß AD model APP/PS1, we investigated circadian, metabolic and amyloid characteristics of female mice and the effects of NOB. Female APP/PS1 mice showed reduced sleep bout duration, and NOB treatment exhibited a trend to improve it. While glucose tolerance was unchanged, female APP/PS1 mice displayed exaggerated oxygen consumption and CO2 production, which was mitigated by NOB. Likewise, cold tolerance in APP/PS1 was impaired relative to WT, and interestingly was markedly enhanced in NOB-treated APP/PS1 mice. Although circadian behavioral rhythms were largely unchanged, real-time qPCR analysis revealed altered expression of several core clock genes by NOB in the cerebral cortex, notably Bmal1, Npas2, and Rora. Moreover, NOB was also able to activate various clock-controlled metabolic genes involved in insulin signaling and mitochondrial function, including Igf1, Glut1, Insr, Irs1, Ucp2, and Ucp4. Finally, we observed that NOB attenuated the expression of several AD related genes including App, Bace1, and ApoE, reduced APP protein levels, and strongly ameliorated Aß pathology in the cortex. Collectively, these results reveal novel genotype differences and importantly beneficial effects of a natural clock-enhancing compound in biological rhythms and related pathophysiology, suggesting the circadian clock as a modifiable target for AD.


Assuntos
Doença de Alzheimer , Ritmo Circadiano/efeitos dos fármacos , Flavonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Ritmo Circadiano/genética , Modelos Animais de Doenças , Feminino , Camundongos
8.
Am J Alzheimers Dis Other Demen ; 36: 15333175211027681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34338033

RESUMO

This paper studied the influence of exercise on the cognitive ability of AD patients and elucidated potential mechanisms. The expression of SNHG14 was validated by qRT-PCR. The cognitive impairment of mice was examined by MWM Test. ELISA tests were applied to discover the influence of SNHG14 on inflammation. Overexpression of SNHG14 was found in AD patients and underexpression of SNHG14 was identified in these AD patients after exercise. In APP/PS1 double transgenic mice, SNHG14 reversed the protective impacts of exercise on escape latency and distance moved. The upregulation of SNHG14 also inhibited the effects of exercise on the percentage of time spent in the target quadrant and times of platform crossing. Besides, overexpression of SNHG14 reversed the repressed expression of IL-6, IL-1ß, and TNF-α. In total, exercise could ameliorate cognitive disorder and inflammation activity by reducing the levels of SNHG14.


Assuntos
Doença de Alzheimer , Transtornos Cognitivos , Cognição , Exercício Físico , RNA Longo não Codificante , Doença de Alzheimer/genética , Animais , Humanos , Camundongos , Camundongos Transgênicos , Condicionamento Físico Animal , RNA Longo não Codificante/genética
9.
Alzheimers Res Ther ; 13(1): 140, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404470

RESUMO

BACKGROUND: Alzheimer's disease, among other neurodegenerative disorders, spans decades in individuals' life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer's disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE-ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. METHODS: We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. RESULTS: The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+, the probability of AD grows from 0.03 to 0.18 (without APOE) and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08-0.6 and 0.3-0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3. CONCLUSIONS: Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach has potential for use in a clinical setting and can easily be updated for novel rare variants and for other populations or confounding factors when appropriate genome-wide association data become available.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Glicoproteínas de Membrana , Receptores Imunológicos , Fatores de Risco
10.
Artigo em Inglês | MEDLINE | ID: mdl-34444269

RESUMO

The clinical manifestations of dementia are often rapidly matched to a specific clinical syndrome, but the underlying neuropathology is not always obvious. A genetic factor often plays an important role in early onset dementia, but there are cases in which the phenotype has a different genetic basis than is assumed. Two patients, at different times, presented to the Memory Clinic because of memory problems and difficulty in performing daily activities and work. Neither caregiver complained of marked behavioural or personality changes, except for apathy. Patients underwent standard dementia evaluation procedures including clinical symptoms, family history, neuroimaging, neuropsychological evaluation, and genetic analysis of selected genes. Based on specific clinical phenotypes and genetic analysis of selected genes, both patients were diagnosed with frontal variant of Alzheimer's disease. The presence of a rare polymorphism in PSEN2 in both patients allowed the discovery that they belong to the same family. This fact reinforced the belief that there is a strong genetic factor responsible for causing dementia in the family. Next-generation sequencing based on a panel of 118 genes was performed to identify other potential genetic factors that may determine the background of the disease. A mutation in the GRN gene was identified, and the previous diagnosis was changed to frontotemporal dementia. The described cases show how important it is to combine all diagnostic tests available in the diagnostic centre, including new generation genetic tests, in order to establish/confirm the pathological background of clinical symptoms of dementia. If there is any doubt about the final diagnosis, persistent efforts should be made to verify the cause.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Testes Neuropsicológicos
11.
Sci Transl Med ; 13(606)2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380771

RESUMO

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid ß (Aß). Here, we describe the Uppsala APP mutation (Δ690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aß42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing ß-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aß, AßUpp1-42Δ19-24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Humanos
12.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361762

RESUMO

Amyloidosis is a group of diseases that includes Alzheimer's disease, prion diseases, transthyretin (ATTR) amyloidosis, and immunoglobulin light chain (AL) amyloidosis. The mechanism of organ dysfunction resulting from amyloidosis has been a topic of debate. This review focuses on the ultrastructure of tissue damage resulting from amyloid deposition and therapeutic insights based on the pathophysiology of amyloidosis. Studies of nerve biopsy or cardiac autopsy specimens from patients with ATTR and AL amyloidoses show atrophy of cells near amyloid fibril aggregates. In addition to the stress or toxicity attributable to amyloid fibrils themselves, the toxicity of non-fibrillar states of amyloidogenic proteins, particularly oligomers, may also participate in the mechanisms of tissue damage. The obscuration of the basement and cytoplasmic membranes of cells near amyloid fibrils attributable to an affinity of components constituting these membranes to those of amyloid fibrils may also play an important role in tissue damage. Possible major therapeutic strategies based on pathophysiology of amyloidosis consist of the following: (1) reducing or preventing the production of causative proteins; (2) preventing the causative proteins from participating in the process of amyloid fibril formation; and/or (3) eliminating already-deposited amyloid fibrils. As the development of novel disease-modifying therapies such as short interfering RNA, antisense oligonucleotide, and monoclonal antibodies is remarkable, early diagnosis and appropriate selection of treatment is becoming more and more important for patients with amyloidosis.


Assuntos
Doença de Alzheimer/patologia , Neuropatias Amiloides Familiares/patologia , Amiloide/imunologia , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Miocárdio/patologia , Nervos Periféricos/patologia , Doenças Priônicas/patologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Amiloide/antagonistas & inibidores , Amiloide/genética , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/imunologia , Benzoxazóis/uso terapêutico , Diflunisal/uso terapêutico , Humanos , Cadeias Leves de Imunoglobulina/genética , Cadeias Leves de Imunoglobulina/metabolismo , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Amiloidose de Cadeia Leve de Imunoglobulina/imunologia , Fatores Imunológicos/uso terapêutico , Miocárdio/imunologia , Fármacos Neuroprotetores/uso terapêutico , Oligonucleotídeos/uso terapêutico , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/imunologia , Pré-Albumina/antagonistas & inibidores , Pré-Albumina/genética , Pré-Albumina/imunologia , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/genética , Doenças Priônicas/imunologia , RNA Interferente Pequeno/uso terapêutico
13.
Alzheimers Res Ther ; 13(1): 143, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429155

RESUMO

BACKGROUND: While still controversial, it has been demonstrated that vascular defects can precede the onset of other AD hallmarks features, making it an important therapeutic target. Given that the protein transthyretin (TTR) has been established as neuroprotective in AD, here we investigated the influence of TTR in the vasculature. METHODS: We evaluated the thickness of the basement membrane and the length of brain microvessels, by immunohistochemistry, in AßPPswe/PS1A246E (AD) transgenic mice and non-transgenic mice (NT) bearing one (TTR+/-) or two (TTR+/+) copies of the TTR gene. The angiogenic potential of TTR was evaluated in vitro using the tube formation assay, and in vivo using the chick chorioallantoic membrane (CAM) assay. RESULTS: AD transgenic mice with TTR genetic reduction, AD/TTR+/-, exhibited a thicker BM in brain microvessels and decreased vessel length than animals with normal TTR levels, AD/TTR+/+. Further in vivo investigation, using the CAM assay, revealed that TTR is a pro-angiogenic molecule, and the neovessels formed are functional. Also, TTR increased the expression of key angiogenic molecules such as proteins interleukins 6 and 8, angiopoietin 2, and vascular endothelial growth factor, by endothelial cells, in vitro, under tube formation conditions. We showed that while TTR reduction also leads to a thicker BM in NT mice, this effect is more pronounced in AD mice than in NT animals, strengthening the idea that TTR is a neuroprotective protein. We also studied the effect of TTR tetrameric stabilization on BM thickness, showing that AD mice treated with the TTR tetrameric stabilizer iododiflunisal (IDIF) displayed a significant reduction of BM thickness and increased vessel length, when compared to non-treated littermates. CONCLUSION: Our in vivo results demonstrate the involvement of TTR in angiogenesis, particularly as a modulator of vascular alterations occurring in AD. Since TTR is decreased early in AD, its tetrameric stabilization can represent a therapeutic avenue for the early treatment of AD through the maintenance of the vascular structure.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Animais , Células Endoteliais , Camundongos , Neuroproteção , Pré-Albumina/genética , Fator A de Crescimento do Endotélio Vascular
14.
Alzheimers Res Ther ; 13(1): 144, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454596

RESUMO

BACKGROUND: Epidemiological studies link vascular disease risk factors such as atherosclerosis, hypertension, and diabetes mellitus with Alzheimer's disease (AD). Whether there are direct links between these conditions to ß-amyloid (Aß) aggregation and tau pathology is uncertain. METHODS: To investigate the possible link between atherosclerosis and AD pathology, we subjected triple transgenic (3 × Tg) AD mice to a high-fat diet (HFD) at 3 months of age, which corresponds to early adulthood in humans. RESULTS: After 9 months of treatment, HFD-treated 3 × Tg mice exhibited worse memory deficits accompanied by blood hypercoagulation, thrombocytosis, and chronic platelet activation. Procoagulant platelets from HFD-treated 3 × Tg mice actively induced the conversion of soluble Aß40 into fibrillar Aß aggregates, associated with increased expression of integrin αIIbß3 and clusterin. At 9 months and older, platelet-associated fibrillar Aß aggregates were observed to obstruct the cerebral blood vessels in HFD-treated 3 × Tg mice. HFD-treated 3 × Tg mice exhibited a greater cerebral amyloid angiopathy (CAA) burden and increased cerebral vascular permeability, as well as more extensive neuroinflammation, tau hyperphosphorylation, and neuron loss. Disaggregation of preexisting platelet micro-clots with humanized GPIIIa49-66 scFv Ab (A11) significantly reduced platelet-associated fibrillar Aß aggregates in vitro and improved vascular permeability in vivo. CONCLUSIONS: These findings suggest that a major contribution of atherosclerosis to AD pathology is via its effects on blood coagulation and the formation of platelet-mediated Aß aggregates that compromise cerebral blood flow and therefore neuronal function. This leads to cognitive decline.


Assuntos
Doença de Alzheimer , Aterosclerose , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Aterosclerose/genética , Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Ativação Plaquetária
15.
Am J Hum Genet ; 108(9): 1647-1668, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34416157

RESUMO

Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.


Assuntos
Proteínas Cromossômicas não Histona/genética , Regulação da Expressão Gênica no Desenvolvimento , Neocórtex/metabolismo , Neurogênese/genética , Neurônios/metabolismo , Locos de Características Quantitativas , Alelos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Diferenciação Celular , Cromatina/química , Cromatina/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Mapeamento Cromossômico , Escolaridade , Feminino , Feto , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurônios/citologia , Neuroticismo , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Cultura Primária de Células , Prognóstico , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Transcriptoma
16.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445342

RESUMO

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Inibidores de Histona Desacetilases/farmacocinética , Histona Desacetilases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/química , Histona Desacetilases/classificação , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroimagem/métodos , Tomografia por Emissão de Pósitrons/métodos , Células Tumorais Cultivadas
17.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445784

RESUMO

Neurodegenerative disorders involve the slow and gradual degeneration of axons and neurons in the central nervous system (CNS), resulting in abnormalities in cellular function and eventual cellular demise. Patients with these disorders succumb to the high medical costs and the disruption of their normal lives. Current therapeutics employed for treating these diseases are deemed palliative. Hence, a treatment strategy that targets the disease's cause, not just the symptoms exhibited, is desired. The synergistic use of nanomedicine and gene therapy to effectively target the causative mutated gene/s in the CNS disease progression could provide the much-needed impetus in this battle against these diseases. This review focuses on Parkinson's and Alzheimer's diseases, the gene/s and proteins responsible for the damage and death of neurons, and the importance of nanomedicine as a potential treatment strategy. Multiple genes were identified in this regard, each presenting with various mutations. Hence, genome-wide sequencing is essential for specific treatment in patients. While a cure is yet to be achieved, genomic studies form the basis for creating a highly efficacious nanotherapeutic that can eradicate these dreaded diseases. Thus, nanomedicine can lead the way in helping millions of people worldwide to eventually lead a better life.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/genética , Animais , Humanos , Nanomedicina/métodos , Doenças Neurodegenerativas/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética
18.
Behav Neurol ; 2021: 3359103, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336000

RESUMO

Objectives: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Certain genes have been identified as important clinical risk factors for AD, and technological advances in genomic research, such as genome-wide association studies (GWAS), allow for analysis of polymorphisms and have been widely applied to studies of AD. However, shortcomings of GWAS include sensitivity to sample size and hereditary deletions, which result in low classification and predictive accuracy. Therefore, this paper proposes a novel deep-learning genomics approach and applies it to multitasking classification of AD progression, with the goal of identifying novel genetic biomarkers overlooked by traditional GWAS analysis. Methods: In this study, we selected genotype data from 1461 subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative, including 622 AD, 473 mild cognitive impairment (MCI), and 366 healthy control (HC) subjects. The proposed deep-learning genomics (DLG) approach consists of three steps: quality control, coding of single-nucleotide polymorphisms, and classification. The ResNet framework was used for the DLG model, and the results were compared with classifications by simple convolutional neural network structure. All data were randomly assigned to one training/validation group and one test group at a ratio of 9 : 1. And fivefold cross-validation was used. Results: We compared classification results from the DLG model to those from traditional GWAS analysis among the three groups. For the AD and HC groups, the accuracy, sensitivity, and specificity of classification were, respectively, 98.78 ± 1.50%, 98.39% ± 2.50%, and 99.44% ± 1.11% using the DLG model, while 71.38% ± 0.63%, 63.13% ± 2.87%, and 85.59% ± 6.66% using traditional GWAS. Similar results were obtained from the other two intergroup classifications. Conclusion: The DLG model can achieve higher accuracy and sensitivity when applied to progression of AD. More importantly, we discovered several novel genetic biomarkers of AD progression, including rs6311 and rs6313 in HTR2A, rs1354269 in NAV2, and rs690705 in RFC3. The roles of these novel loci in AD should be explored in future research.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Aprendizado Profundo , Idoso , Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Imageamento por Ressonância Magnética
19.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371878

RESUMO

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.


Assuntos
Doença de Alzheimer/prevenção & controle , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Plasma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ração Animal , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Quinase 5 Dependente de Ciclina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Transdução de Sinais , Secagem por Atomização , Sus scrofa , Proteínas tau/metabolismo
20.
Neuron ; 109(15): 2363-2365, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34352209

RESUMO

In this issue of Neuron, Shi et al. (2021) show a protective role for the low-density lipoprotein receptor (LDLR) in tau pathology. Brain overexpression of LDLR lowers apolipoprotein E (apoE), suppresses microglial activation, preserves myelin, and ameliorates neurodegeneration, pointing the way toward potential new therapies.


Assuntos
Doença de Alzheimer , Tauopatias , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Humanos , Lipoproteínas LDL , Receptores de LDL/genética , Receptores de LDL/metabolismo , Tauopatias/genética
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