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  1. Article: Editorial: Metabolic signaling dysregulation and cognitive impairments in aging and Alzheimer's disease, volume II.

    Ma, Tao / Chang, Raymond Chuen-Chung / Macauley, Shannon L

    Frontiers in aging neuroscience

    2023  Volume 15, Page(s) 1150101

    Language English
    Publishing date 2023-02-03
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2023.1150101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem.

    Macauley, Shannon L

    Pediatric endocrinology reviews : PER

    2016  Volume 13 Suppl 1, Page(s) 639–648

    Abstract: Abstract Lysosomal storage diseases (LSDs) are a group of 40-50 rare monogenic disorders that result in disrupted lysosomal function and subsequent lysosomal pathology. Depending on the protein or enzyme deficiency associated with each disease, LSDs ... ...

    Abstract Abstract Lysosomal storage diseases (LSDs) are a group of 40-50 rare monogenic disorders that result in disrupted lysosomal function and subsequent lysosomal pathology. Depending on the protein or enzyme deficiency associated with each disease, LSDs affect an array of organ systems and elicit a complex set of secondary disease mechanisms that make many of these disorders difficult to fully treat. The etiology of most LSDs is known and the innate biology of lysosomal enzymes favors therapeutic intervention, yet most attempts at treating LSDs with enzyme replacement strategies fall short of being curative. Even with the advent of more sophisticated approaches, like substrate reduction therapy, pharmacologic chaperones, gene therapy or stem cell therapy, comprehensive treatments for LSDs have yet to be achieved. Given the limitations with individual therapies, recent research has focused on using a combination approach to treat LSDs. By coupling protein-, cell-, and gene- based therapies with small molecule drugs, researchers have found greater success in eradicating the clinical features of disease. This review seeks to discuss the positive and negatives of singular therapies used to treat LSDs, and discuss how, in combination, studies have demonstrated a more holistic benefit on pathological and functional parameters. By optimizing routes of delivery, therapeutic timing, and targeting secondary disease mechanisms, combination therapy represents the future for LSD treatment.
    MeSH term(s) Bone Marrow Transplantation ; Combined Modality Therapy ; Enzyme Replacement Therapy/methods ; Genetic Therapy/methods ; Humans ; Lysosomal Storage Diseases/therapy
    Language English
    Publishing date 2016-06
    Publishing country Israel
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2434390-0
    ISSN 1565-4753
    ISSN 1565-4753
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The Interaction Between Sleep and Metabolism in Alzheimer's Disease: Cause or Consequence of Disease?

    Carroll, Caitlin M / Macauley, Shannon L

    Frontiers in aging neuroscience

    2019  Volume 11, Page(s) 258

    Abstract: Alzheimer's disease (AD) is the most common form of dementia and affects over 45 million people worldwide. Both type-2-diabetes (T2D), a metabolic condition associated with aging, and disrupted sleep are implicated in the pathogenesis of AD, but how ... ...

    Abstract Alzheimer's disease (AD) is the most common form of dementia and affects over 45 million people worldwide. Both type-2-diabetes (T2D), a metabolic condition associated with aging, and disrupted sleep are implicated in the pathogenesis of AD, but how sleep and metabolism interact to affect AD progression remains unclear. In the healthy brain, sleep/wake cycles are a well-coordinated interaction between metabolic and neuronal activity, but when disrupted, are associated with a myriad of health-related issues, including metabolic syndrome, cardiovascular disease, T2D, and AD. Therefore, this review will explore our current understanding of the relationship between metabolism, sleep, and AD-related pathology to identify the causes and consequences of disease progression in AD. Moreover, sleep disturbances and metabolic dysfunction could serve as potential therapeutic targets to mitigate the increased risk of AD in individuals with T2D or offer a novel approach for treating AD.
    Language English
    Publishing date 2019-09-20
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2019.00258
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Kir6.2-K

    Constantino, Nicholas J / Carroll, Caitlin M / Williams, Holden C / Yuede, Carla M / Sheehan, Patrick W / Andy Snipes, J / Musiek, Erik S / Johnson, Lance A / Macauley, Shannon L

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated ... ...

    Abstract Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (K
    Highlights: Glycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. With Kir6.2-K
    Language English
    Publishing date 2024-02-28
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.23.581817
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: APOE4

    Lee, Sangderk / Williams, Holden C / Gorman, Amy A / Devanney, Nicholas A / Harrison, Douglas A / Walsh, Adeline E / Goulding, Danielle S / Tuck, Tony / Schwartz, James L / Zajac, Diana J / Macauley, Shannon L / Estus, Steven / Julia, Tcw / Johnson, Lance A / Morganti, Josh M

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer's disease (AD). Across the CNS, astrocytes are the predominant expressor ... ...

    Abstract Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer's disease (AD). Across the CNS, astrocytes are the predominant expressor of
    Language English
    Publishing date 2023-02-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.06.527204
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Recent Advances from the Bench Toward the Bedside in Alzheimer's Disease.

    Macauley, Shannon L / Holtzman, David M

    EBioMedicine

    2015  Volume 2, Issue 2, Page(s) 94–95

    MeSH term(s) Alzheimer Disease/economics ; Alzheimer Disease/pathology ; Alzheimer Disease/therapy ; Amyloid beta-Peptides/metabolism ; Humans ; Plaque, Amyloid/pathology ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; MAPT protein, human ; tau Proteins
    Language English
    Publishing date 2015-01-09
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2851331-9
    ISSN 2352-3964 ; 2352-3964
    ISSN (online) 2352-3964
    ISSN 2352-3964
    DOI 10.1016/j.ebiom.2015.01.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7090: Show issues Location:
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  7. Article ; Online: Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV

    Pait, Morgan C / Kaye, Sarah D / Su, Yixin / Kumar, Ashish / Singh, Sangeeta / Gironda, Stephen C / Vincent, Samantha / Anwar, Maria / Carroll, Caitlin M / Snipes, James Andy / Lee, Jingyun / Furdui, Cristina M / Deep, Gagan / Macauley, Shannon L

    Journal of extracellular vesicles

    2023  Volume 13, Issue 1, Page(s) e12398

    Abstract: Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD ... ...

    Abstract Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EV
    MeSH term(s) Female ; Animals ; Mice ; Proteome ; Extracellular Fluid ; Extracellular Vesicles ; Microglia ; Proteomics ; Alzheimer Disease ; Hippocampus ; Plaque, Atherosclerotic
    Chemical Substances Proteome
    Language English
    Publishing date 2023-12-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2683797-3
    ISSN 2001-3078 ; 2001-3078
    ISSN (online) 2001-3078
    ISSN 2001-3078
    DOI 10.1002/jev2.12398
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.

    Rhea, Elizabeth M / Leclerc, Manon / Yassine, Hussein N / Capuano, Ana W / Tong, Han / Petyuk, Vladislav A / Macauley, Shannon L / Fioramonti, Xavier / Carmichael, Owen / Calon, Frederic / Arvanitakis, Zoe

    Aging and disease

    2023  

    Abstract: Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, ... ...

    Abstract Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.
    Language English
    Publishing date 2023-08-17
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2625789-0
    ISSN 2152-5250
    ISSN 2152-5250
    DOI 10.14336/AD.2023.0814
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV-ISF) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

    Pait, Morgan C / Kaye, Sarah D / Su, Yixin / Kumar, Ashish / Singh, Sangeeta / Gironda, Stephen C / Vincent, Samantha / Anwar, Maria / Carroll, Caitlin M / Snipes, J Andy / Lee, Jingyun / Furdui, Cristina M / Deep, Gagan / Macauley, Shannon L

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. Circulating EVs are protected from degradation, making them attractive AD biomarkers. ... ...

    Abstract Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. Circulating EVs are protected from degradation, making them attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labeling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g. APPswe,PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with A deposition. Genotype, age, and Aβ deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse- EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.
    Language English
    Publishing date 2023-03-12
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.10.532133
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design.

    Ruggiero, Alistaire D / Vemuri, Ravichandra / Blawas, Megan / Long, Masha / DeStephanis, Darla / Williams, Abigail G / Chen, Haiying / Justice, Jamie N / Macauley, Shannon L / Day, Steven M / Kavanagh, Kylie

    GeroScience

    2023  Volume 45, Issue 5, Page(s) 2785–2803

    Abstract: Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow ... ...

    Abstract Cellular senescence increases with aging and results in secretion of pro-inflammatory factors that induce local and systemic tissue dysfunction. We conducted the first preclinical trial in a relevant middle-aged nonhuman primate (NHP) model to allow estimation of the main translatable effects of the senolytic combination dasatinib (D) and quercetin (Q), with and without caloric restriction (CR). A multi-systemic survey of age-related changes, including those on immune cells, adipose tissue, the microbiome, and biomarkers of systemic organ and metabolic health are reported. Age-, weight-, sex-, and glycemic control-matched NHPs (D + Q, n = 9; vehicle [VEH] n = 7) received two consecutive days of D + Q (5 mg/kg + 50 mg/kg) monthly for 6 months, where in month six, a 10% CR was implemented in both D + Q and VEH NHPs to induce equal weight reductions. D + Q reduced senescence marker gene expressions in adipose tissue and circulating PAI-1 and MMP-9. Improvements were observed in immune cell types with significant anti-inflammatory shifts and reductions in microbial translocation biomarkers, despite stable microbiomes. Blood urea nitrogen showed robust improvements with D + Q. CR resulted in significant positive body composition changes in both groups with further improvement in immune cell profiles and decreased GDF15 (p = 0.05), and the interaction of D + Q and CR dramatically reduced glycosylated hemoglobin A1c (p = 0.03). This work indicates that 6 months of intermittent D + Q exposure is safe and may combat inflammaging via immune benefits and improved intestinal barrier function. We also saw renal benefits, and with CR, improved metabolic health. These data are intended to provide direction for the design of larger controlled intervention trials in older patients.
    MeSH term(s) Animals ; Humans ; Middle Aged ; Aged ; Dasatinib/pharmacology ; Quercetin/pharmacology ; Senotherapeutics ; Clinical Trials as Topic ; Aging ; Inflammation ; Biomarkers ; Primates
    Chemical Substances Dasatinib (RBZ1571X5H) ; Quercetin (9IKM0I5T1E) ; Senotherapeutics ; Biomarkers
    Language English
    Publishing date 2023-06-01
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2886586-8
    ISSN 2509-2723 ; 2509-2715
    ISSN (online) 2509-2723
    ISSN 2509-2715
    DOI 10.1007/s11357-023-00830-5
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