- Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of Parkinson's disease. [Journal Article]
- HMHum Mol Genet 2018 Feb 14
- We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, t...
We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (< 1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (> 10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation. We discovered that α-syn expression phenocopies the high iron condition: under the low iron condition (< 1 µM), α-syn inhibits Snx3-retromer-mediated recycling of Fet3/Ftr1 and instead shunts Fet3/Ftr1 into the multivesicular body (MVB) pathway to the vacuole. α-syn inhibits recycling by blocking the association of Snx3-mCherry molecules with endocytic vesicles, possibly by interfering with the binding of Snx3 to phosphatidylinositol-3-monophosphate (PI3P). In C. elegans, transgenic worms expressing α-syn exhibit an age-dependent degeneration of dopaminergic neurons that is partially rescued by the iron chelator desferoxamine (DFO). This implies that α-syn-expressing dopaminergic neurons are susceptible to changes in iron neurotoxicity with age, whereby excess iron enhances α-syn-induced neurodegeneration. In vivo genetic analysis indicates that α-syn dysregulates iron homeostasis in worm dopaminergic neurons, possibly by inhibiting SNX-3-mediated recycling of a membrane-bound ortholog of Cp (F21D5.3), the iron exporter ferroportin (FPN1.1), or both.
- Massively parallel C. elegans tracking provides multi-dimensional fingerprints for phenotypic discovery. [Journal Article]
- JNJ Neurosci Methods 2018 Feb 13
- CONCLUSIONS: The WF-NTP extends significantly the power of existing automated platforms by combining enhanced optical imaging techniques with an advanced software platform. This approach will further extend the scope and utility of C. elegans as a model organism.
- Caregiver Reactions to Dementia Symptoms: Effects on Coping Repertoire and Mental Health. [Journal Article]
- IMIssues Ment Health Nurs 2018 Feb 16; :1-6
- Currently, 15 million informal caregivers, most of whom are women, provide care for older adults with dementia (Alzheimer's Disease Association, 2016). Caregiving for these individuals often creates ...
Currently, 15 million informal caregivers, most of whom are women, provide care for older adults with dementia (Alzheimer's Disease Association, 2016). Caregiving for these individuals often creates distress and may adversely affect female caregivers' psychosocial and spiritual well-being. Approximately 35% of dementia caregivers complain of health deterioration after initiating caregiving responsibilities as compared to 19% of caregivers of older adults who do not have dementia (Alzheimer's Disease Association, 2016). Persons with dementia exhibit symptoms and behaviors that often are challenging for their caregivers. The way that caregivers react to these symptoms and behaviors may affect their coping repertoire and their mental health. Adequate evaluation of caregiver reactions to symptoms of dementia will provide information useful for developing targeted interventions to promote optimal health of female dementia caregivers and to potentially postpone the need for nursing home or long-term placement of the care recipient.
- Diagnosing dementia in lower educated older persons: validation of a Brazilian Portuguese version of the Rowland Universal Dementia Assessment Scale (RUDAS). [Journal Article]
- RBRev Bras Psiquiatr 2018 Feb 15; :0
- CONCLUSIONS: The RUDAS-BR is as accurate as the MMSE in screening for dementia. RUDAS-BR scores were not influenced by education. The RUDAS-BR may improve the cognitive assessment of older persons who are illiterate or of lower educational attainment.
- Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer's disease. [Review]
- NRNeural Regen Res 2018; 13(1):19-25
- Alzheimer's disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies tha...
Alzheimer's disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.
- Reduced integration and improved segregation of functional brain networks in Alzheimer's disease. [Journal Article]
- JNJ Neural Eng 2018 Feb 16; 15(2):026023
- CONCLUSIONS: These findings may contribute to the development of EEG network-based test that could strengthen results obtained from currently-used neurophysiological tests in neurodegenerative diseases.
- Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases. [Journal Article]
- DMDrug Metab Rev 2018 Feb 16; :1-14
- Cytochromes P450 (CYPs) constitute a family of enzymes that can be found in the endoplasmic reticulum (ER), mitochondria or the cell surface of the cells. CYPs are characterized by carrying out the o...
Cytochromes P450 (CYPs) constitute a family of enzymes that can be found in the endoplasmic reticulum (ER), mitochondria or the cell surface of the cells. CYPs are characterized by carrying out the oxidation of organic compounds and they are mainly recognized as mediators of the biotransformation of xenobiotics to polar hydrophilic metabolites that can be eliminated from the organism. However, these enzymes play a key role in many other physiological processes, being involved in diverse indispensable metabolic pathways since they metabolize many endogenous substrates. Various CYP isoforms are expressed in the brain, and it is believed that this could be in part due to the particular function of brain CYPs. In the brain, CYPs are involved in the cholesterol turnover, the biosynthesis of dopamine, serotonin, morphine, hormones, and protective lipid mediators (epoxyeicosatrienoic acids), in addition to their already recognized role in xenobiotics detoxification and psychotropic drug metabolism. Increasing evidence suggests that this group of enzymes is fundamental for the normal functioning and maintenance of brain homeostasis. This review is focused on highlighting the importance of CYP-mediated endogenous metabolism in the central nervous system (CNS) and its relationship with recent findings regarding CYP involvement in neurodegenerative diseases. Some therapeutic approaches focused on CYP regulation are also discussed.
- Network pharmacology-based screening of the active ingredients and potential targets of the genus of Pithecellobium marthae (Britton & Killip) Niezgoda & Nevl for application to Alzheimer's disease. [Journal Article]
- NPNat Prod Res 2018 Feb 16; :1-4
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β-amyloid (Aβ), and neuronal loss. Given the prevalence of AD a...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β-amyloid (Aβ), and neuronal loss. Given the prevalence of AD and the lack of effective long-term therapies, there is a pressing need to discover viable leads that can be developed into clinically approved drugs with disease-modifying effects. The analysis of current reported literatures confirms the importance of the plants of Pithecellobium genus as candidate against AD. Hence, it is necessary to identify selective anti-dementia agents from this genus. To explore potential compounds with marked effect on AD in Pithecellobium genus, a compound database based on the methods of network pharmacology prediction was established in this paper by constructing the compound-disease target network. The result showed that the most effective compound in the plants of this genus might be (7'R,8'R)-7'-methoxyl strebluslignanol, and the most potential target might be Macrophage colony-stimulating factor 1 receptor.
- Differential Binding of Human ApoE Isoforms to Insulin Receptor is Associated with Aberrant Insulin Signaling in AD Brain Samples. [Journal Article]
- NMNeuromolecular Med 2018 Feb 15
- Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), where inheritance of this isoform predisposes development of AD in a gene dose-dependent manner. ...
Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), where inheritance of this isoform predisposes development of AD in a gene dose-dependent manner. Although the mode of action of ApoE4 on AD onset and progression remains unknown, we have previously shown that ApoE4, and not ApoE3 expression, resulted in insulin signaling deficits in the presence of amyloid beta (Aβ). However, these reports were not conducted with clinical samples that more accurately reflect human disease. In this study, we investigated the effect of ApoE genotype on the insulin signaling pathway in control and AD human brain samples. We found that targets of the insulin signaling pathway were attenuated in AD cases, regardless of ApoE isoform. We also found a decrease in GluR1 subunit expression, and an increase NR2B subunit expression in AD cases, regardless of ApoE isoform. Lastly, we observed that more insulin receptor (IR) was immunoprecipitated in control cases, and more Aβ was immunoprecipitated with AD cases. But, when comparing among AD cases, we found that more IR was immunoprecipitated with ApoE3 than ApoE4, and more Aβ was immunoprecipitated with ApoE4 than ApoE3. Our results suggest that the difference in IR binding and effect on protein expression downstream of the IR may affect onset and progression of AD.
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- Who will remain tremor dominant? The possible role of cognitive reserve in the time course of two common Parkinson's disease motor subtypes. [Journal Article]
- JNJ Neural Transm (Vienna) 2018 Feb 15
- In a prospective 5-year study among Parkinson's disease (PD) tremor-dominant (TD) patients, we investigated who will remain TD and who will later convert into the postural instability gait difficulty...
In a prospective 5-year study among Parkinson's disease (PD) tremor-dominant (TD) patients, we investigated who will remain TD and who will later convert into the postural instability gait difficulty (PIGD) phenotype. At follow-up, 38% were still considered TD. At baseline the TD non-convertors had more years of education and better cognitive function than the convertors and significantly smaller deterioration in gait, balance, cognitive function and other non-motor symptoms. These results highlight the potential role of cognition in protecting against the development of PIGD symptoms.