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1.
Curr Aging Sci ; 13(1): 2-3, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362272
2.
3.
Transl Psychiatry ; 10(1): 81, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123156

RESUMO

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

5.
Transl Psychiatry ; 10(1): 47, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066688

RESUMO

Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-ß peptide (Aß) generated from its precursor protein (APP) by ß-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases- Adamalysins) precludes the generation of toxic Aß and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.

6.
Mol Psychiatry ; 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31942037

RESUMO

Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid- ß (Aß) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aß is a neurotoxic peptide excised from the amyloid-ß precursor protein (APP) by ß-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aß (Aß40 and Aß42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of ~55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aß42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.

7.
Sci Rep ; 9(1): 18261, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31797941

RESUMO

Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer's disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels. We cultured and differentiated human neuroblastoma (SK-N-SH) cells to neuronal cells with all-trans retinoic acid (ATRA). We exposed cultures for one week to lithium chloride or distilled water, extracted total RNA, depleted ribosomal RNA and performed whole-transcriptome RT-sequencing. We analyzed results by RNA length and type. We further analyzed expression and protein interaction networks between selected Li-altered protein-coding RNAs and common AD-associated gene products. Lithium changed expression of RNAs in both non-specific (inverse to sequence length) and specific (according to RNA type) fashions. The non-coding small nucleolar RNAs (snoRNAs) were subject to the greatest length-adjusted Li influence. When RNA length effects were taken into account, microRNAs as a group were significantly less likely to have had levels altered by Li treatment. Notably, several Li-influenced protein-coding RNAs were co-expressed or produced proteins that interacted with several common AD-associated genes and proteins. Lithium's modification of RNA levels depends on both RNA length and type. Li activity on snoRNA levels may pertain to bipolar disorders while Li modification of protein coding RNAs may be relevant to AD.

8.
Science ; 366(6465): 581, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672886
9.
Sci Rep ; 9(1): 13990, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570736

RESUMO

Memory loss is one of the most tragic symptoms of Alzheimer's disease. Our laboratory has recently demonstrated that 'i-Extract' of Ashwagandha (Withania somnifera) restores memory loss in scopolamine (SC)-induced mice. The prime target of i-Extract is obscure. We hypothesize that i-Extract may primarily target muscarinic subtype acetylcholine receptors that regulate memory processes. The present study elucidates key target(s) of i-Extract via cellular, biochemical, and molecular techniques in a relevant amnesia mouse model and primary hippocampal neuronal cultures. Wild type Swiss albino mice were fed i-Extract, and hippocampal cells from naïve mice were treated with i-Extract, followed by muscarinic antagonist (dicyclomine) and agonist (pilocarpine) treatments. We measured dendritic formation and growth by immunocytochemistry, kallikrein 8 (KLK8) mRNA by reverse transcription polymerase chain reaction (RT-PCR), and levels of KLK8 and microtubule-associated protein 2, c isoform (MAP2c) proteins by western blotting. We performed muscarinic receptor radioligand binding. i-Extract stimulated an increase in dendrite growth markers, KLK8 and MAP2. Scopolamine-mediated reduction was significantly reversed by i-Extract in mouse cerebral cortex and hippocampus. Our study identified muscarinic receptor as a key target of i-Extract, providing mechanistic evidence for its clinical application in neurodegenerative cognitive disorders.

10.
J Biol Chem ; 294(24): 9365, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201240
12.
Mol Neurobiol ; 56(10): 7173-7187, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30993533

RESUMO

Although Alzheimer's disease (AD) is an international health research priority for our aging population, little therapeutic progress has been made. This lack of progress may be partially attributable to disease heterogeneity. Previous studies have identified an inverse association of cancer and AD, suggesting that cancer history may be one source of AD heterogeneity. These findings are particularly interesting in light of the number of common risk factors and two-hit models hypothesized to commonly drive both diseases. We reviewed the ten hallmark biological alterations of cancer cells to investigate overlap with the AD literature and identified overlap of all ten hallmarks in AD, including (1) potentially common underlying risk factors, such as increased inflammation, deregulated cellular energetics, and genome instability; (2) inversely regulated mechanisms, including cell death and evading growth suppressors; and (3) functions with more complex, pleiotropic mechanisms, some of which may be stage-dependent in AD, such as cell adhesion/contact inhibition and angiogenesis. Additionally, we discuss the recent observation of a biological link between cancer and AD neuropathology. Finally, we address the therapeutic implications of this topic. The significant overlap of functional pathways and molecules between these diseases, some similarly and some oppositely regulated or functioning in each disease, supports the need for more research to elucidate cancer-related AD genetic and functional heterogeneity, with the aims of better understanding AD risk mediators, as well as further exploring the potential for some types of drug repurposing towards AD therapeutic development.


Assuntos
Doença de Alzheimer/complicações , Neoplasias/complicações , Idade de Início , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Animais , Encéfalo/patologia , Instabilidade Genômica , Humanos , Neoplasias/genética , Neoplasias/terapia , Transdução de Sinais
13.
Front Psychiatry ; 10: 165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31024350

RESUMO

The most replicated neuroanatomical finding in autism is the tendency toward brain overgrowth, especially in younger children. Research shows that both gray and white matter are enlarged. Proposed mechanisms underlying brain enlargement include abnormal inflammatory and neurotrophic signals that lead to excessive, aberrant dendritic connectivity via disrupted pruning and cell adhesion, and enlargement of white matter due to excessive gliogenesis and increased myelination. Amyloid-ß protein precursor (ßAPP) and its metabolites, more commonly associated with Alzheimer's disease (AD), are also dysregulated in autism plasma and brain tissue samples. This review highlights findings that demonstrate how one ßAPP metabolite, secreted APPα, and the ADAM family α-secretases, may lead to increased brain matter, with emphasis on increased white matter as seen in autism. sAPPα and the ADAM family α-secretases contribute to the anabolic, non-amyloidogenic pathway, which is in contrast to the amyloid (catabolic) pathway known to contribute to Alzheimer disease. The non-amyloidogenic pathway could produce brain enlargement via genetic mechanisms affecting mRNA translation and polygenic factors that converge on molecular pathways (mitogen-activated protein kinase/MAPK and mechanistic target of rapamycin/mTOR), promoting neuroinflammation. A novel mechanism linking the non-amyloidogenic pathway to white matter enlargement is proposed: α-secretase and/or sAPPα, activated by ERK receptor signaling activates P13K/AKt/mTOR and then Rho GTPases favoring myelination via oligodendrocyte progenitor cell (OPC) activation of cofilin. Applying known pathways in AD to autism should allow further understanding and provide options for new drug targets.

14.
J Alzheimers Dis ; 68(1): 115-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689563

RESUMO

The degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine ß-hydroxylase staining and increased amyloid-ß load in the aged group, and the proportion of potentially toxic amyloid-ß42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.

15.
Mol Psychiatry ; 24(3): 345-363, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30470799

RESUMO

In addition to the devastating symptoms of dementia, Alzheimer's disease (AD) is characterized by accumulation of the processing products of the amyloid-ß (Aß) peptide precursor protein (APP). APP's non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3'-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5'-UTR to upregulate APP translation and Aß production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a "FeAR" (Fe, APP, RNA) nexus in the APP 5'-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a "healthy FeAR" exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Regiões 5' não Traduzidas , Encéfalo/metabolismo , Linhagem Celular , Células HEK293 , Células HeLa , Humanos , Cultura Primária de Células , Biossíntese de Proteínas , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ativação Transcricional , Regulação para Cima
16.
Alzheimers Dement (N Y) ; 4: 488-498, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30338290

RESUMO

Introduction: Glucocorticoid-induced leucine zipper is a regulatory protein that sequesters activated nuclear factor-kappa B p65. Previously, we showed that rationally designed analogs of the p65-binding domain of glucocorticoid-induced leucine zipper, referred to as glucocorticoid-induced leucine zipper analogs (GAs), inhibited amyloid ß-induced metabolic activity and inflammatory cytokines in mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in an Alzheimer's disease model. Methods: GA and control peptides were synthesized covalently as peptide amides with the cell-penetrating agent. C57Bl/6J mice induced with lipopolysaccharide-mediated neuroinflammation (250 mg/kg i.p/day for six days) were treated on alternate days with GA-1, GA-2, or control peptides (25 mg/kg i.v). Brain tissues were assessed for gliosis, cytokines, and antiapoptotic factors. Results: The brain tissues of GA-1- and GA-2-treated mice exhibited significantly reduced gliosis, suppressed inflammatory cytokines, and elevated antiapoptotic factors. Discussion: The antineuroinflammatory effects of GA suggest potential therapeutic application for Alzheimer's disease.

17.
J Neurochem ; 147(6): 831-848, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30152072

RESUMO

For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD-like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose- and time-dependently blocks the protein translation of amyloid precursor protein (APP) and heavy-chain Ferritin (H-Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H-Ferritin are post-transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5'-untranslated regions (5'-UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5'-UTR-activity of APP and H-Ferritin, presumably via increased iron responsive proteins-iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+ -specific probes (RhoNox-1 and IP-1) and ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS), we show that loss of the protective axis of APP and H-Ferritin resulted in unchecked accumulation of redox-active ferrous iron (Fe2+ ) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn-induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn-mediated suppression of APP and H-Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn-induced neurotoxicity is partly attributable to the translational inhibition of APP and H-Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.


Assuntos
Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Apoferritinas/antagonistas & inibidores , Ferro/metabolismo , Intoxicação por Manganês/metabolismo , Regiões 5' não Traduzidas , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apoferritinas/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Modificação Traducional de Proteínas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
19.
Neurotoxicology ; 68: 126-132, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29981765

RESUMO

BACKGROUND: The lead (Pb) exposure crisis in Flint, Michigan has passed from well-publicized event to a footnote, while its biological and social impact will linger for lifetimes. Interest in the "water crisis" has dropped to pre-event levels, which is neither appropriate nor safe. Flint's exposure was severe, but it was not unique. Problematic Pb levels have also been found in schools and daycares in 42 states in the USA. The enormity of Pb exposure via municipal water systems requires multiple responses. Herein, we focus on addressing a possible answer to long-term sequelae of Pb exposure. We propose "4R's" (remediation, renovation, reallocation, and research) against the Pb crisis that goes beyond a short-term fix. Remediation for affected individuals must continue to provide clean water and deal with both short and long-term effects of Pb exposure. Renovation of current water delivery systems, at both system-wide and individual site levels, is necessary. Reallocation of resources is needed to ensure these two responses occur and to get communities ready for potential sequelae of Pb exposure. Finally, properly focused research can track exposed individuals and illuminate latent (presumably epigenetic) results of Pb exposure and inform further resource reallocation. CONCLUSION: Motivation to act by not only the general public but also by scientific and medical leaders must be maintained beyond initial news cycle spikes and an annual follow-up story. Environmental impact of Pb contamination of drinking water goes beyond one exposure incident in an impoverished and forgotten Michigan city. Population effects must be addressed long-term and nationwide.


Assuntos
Exposição Ambiental/prevenção & controle , Intoxicação por Chumbo/prevenção & controle , Poluentes Químicos da Água , Água Potável , Monitoramento Ambiental , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
20.
Sci Rep ; 8(1): 9928, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29967374

RESUMO

The multitude of molecular pathways underlying memory impairment in neurological disorders and aging-related disorders has been a major hurdle against therapeutic targeting. Over the years, neuronal growth promoting factors, intracellular kinases, and specific transcription factors, particularly cyclic AMP response element-binding protein (CREB), have emerged as crucial players of memory storage, and their disruption accompanies many cognitive disabilities. However, a molecular link that can influence these major players and can be a potential recovery target has been elusive. Recent reports suggest that extracellular cues at the synapses might evoke an intracellular signaling cascade and regulate memory function. Herein, we report novel function of an extracellular serine protease, kallikrein 8 (KLK8/Neuropsin) in regulating the expression of microtubule associated dendrite growth marker microtubule-associated protein (MAP2)c, dendrite architecture and protein kinase A (PKA)-CREB signaling. Both knockdown of KLK8 via siRNA transfection in mouse primary hippocampal neurons and via intra-hippocampal administration of KLK8 antisense oligonucleotides in vivo reduced expression of MAP2c, dendrite length, dendrite branching and spine density. The KLK8 mediated MAP2c deficiency in turn inactivated PKA and downstream transcription factor phosphorylated CREB (pCREB), leading to downregulation of memory-linked genes and consequent impaired memory consolidation. These findings revealed a protease associated novel pathway of memory impairment in which KLK8 may act as a "regulator of regulators", suggesting its exploration as an important therapeutic target of memory disorders.


Assuntos
Dendritos/metabolismo , Hipocampo/metabolismo , Calicreínas/metabolismo , Transtornos da Memória/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Transdução de Sinais , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dendritos/fisiologia , Regulação da Expressão Gênica , Hipocampo/fisiopatologia , Masculino , Memória , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteólise
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